ATXN3 Data Analysis

HGNC Gene Name: ataxin 3
HGNC Gene Symbol: ATXN3
Identifiers: hgnc:7106 NCBIGene:4287 uniprot:P54252
Orthologs: rgd:621567
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for ATXN3
Number of Papers: 787 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)
TP53	tumor protein p53	0.262	BioGRID INDRA (14) Reactome (6)	0.04	0.13	5.81e-01
DUSP29	dual specificity phosphatase 29	0.257
PPM1D	protein phosphatase, Mg2+/Mn2+ dependent 1D	-0.251	Reactome (3)	-0.02	-0.18	9.02e-01
HIVEP2	HIVEP zinc finger 2	0.237		0.05	0.17	5.68e-01
RMDN3	regulator of microtubule dynamics 3	0.237		-0.17	-1.05	2.99e-03
NDUFA9	NADH:ubiquinone oxidoreductase subunit A9	0.235		-0.19	-1.14	1.05e-03
KRT2	keratin 2	0.23

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with ATXN3using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value

Literature Mining

INDRA was used to automatically assemble known mechanisms related to ATXN3 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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ATXN3 deubiquitinates STUB1. 10 / 20

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Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating the reaction.

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We next tested whether the presence of UbcH5c, which is needed to polyubiquitinate HSP90, reduced the amount of ataxin-3 needed to deubiquitinate Ub-CHIP in active ubiquitination assays.

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Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains.

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Intriguingly, deubiquitination of Ub-CHIP by ataxin-3 correlated temporally with the accumulation of ubiquitinated substrates and occurred whether ataxin-3 had a normal or expanded polyglutamine domain (XREF_FIG).

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Upon completion of substrate ubiquitination, as determined by chain length, ataxin-3 presumably binds ubiquitinated substrate through its UIMs and deubiquitinates CHIP, thus terminating the reaction (XREF_FIG) [XREF_BIBR].

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Importantly, ataxin-3 deubiquitinates CHIP, terminating CHIP-substrate interaction; polyQ expansion of ataxin-3 increases its affinity for CHIP and decreases CHIP levels in SCA3 mice, suggesting a surprising role for coordinated regulation of CHIP and ataxin-3 as well as dysregulation of this process in SCA3.

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Evidence further supporting this notion that the ability of ataxin-3 to deubiquitinate CHIP is coupled to the ligase activity of CHIP, came from assays in which ataxin-3-mediated deubiquitination of CHIP did not occur until after poly-Ub conjugates on substrate proteins had attained a certain length.

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The above results do not exclude the possibility that ubiquitin chains per se rather than polyubiquitinated substrates facilitate deubiquitination of CHIP by ataxin-3.

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To determine whether deubiquitination of Ub-CHIP by ataxin-3 requires the presence of ubiquitinated substrate, we performed CHIP ubiquitination reactions with increasing concentrations of HSP90 as substrate, in the presence or absence of ataxin-3 and the chain elongating E2, UbcH5c (XREF_FIG), then assessed the ubiquitin state of CHIP at the end of the reaction.

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Intriguingly, monoubiquitination of CHIP appears to enhance the interaction between ataxin-3 and CHIP, and when bound, ataxin-3 can now deubiquitinate CHIP.

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ATXN3 deubiquitinates PRKN. 8 / 8

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Ataxin-3, a DUB associated with Machado-Joseph disease, was reported to reduce the self ubiquitination of parkin, a familiar form of Parkinson disease associated E3 ubiquitin-ligase [XREF_BIBR].

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Thus, it is likely that Ataxin-3 inhibits parkin autoubiquitination by intercepting the Ub from E2 ~ Ub with its own active site thiol and the resulting DUB thioester intermediate is protected from hydrolysis by the stable ternary complex.

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Interestingly, although ataxin-3 deubiquitinates parkin, parkin is unable to ubiquitinate ataxin-3.

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Wild-type and polyQ expanded ataxin-3 deubiquitinate parkin directly and parkin ubiquitinates and facilitates the clearance of wild-type and mutant ataxin-2 and ataxin-3 by proteasomal degradation [XREF_BIBR - XREF_BIBR].

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Ataxin-3 is proposed to reduce this self ubiquitination of Parkin by removal of the isopeptide linkage [XREF_BIBR].

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With parkin, ataxin-3 was unable to remove individual Ub moieties or preformed Ub chains after they had formed, suggesting that ataxin-3 was deubiquitinating parkin through a more unconventional mechanism.

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Recently, it has been shown that ataxin-3 deubiquitinates C-terminus of Hsp70 interacting protein (CHIP) and parkin XREF_BIBR, XREF_BIBR.

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?Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells

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ATXN3 deubiquitinates CHEK1. 4 / 4

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Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance.

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We discover that, under unperturbed conditions and upon DNA damage, deubiquitination of Chk1 by ATX3 limits its polyubiquitination and subsequent degradation mediated by CUL1- and CUL4A- containing E3 ligase complexes, thus promoting Chk1 stabilization and further checkpoint signaling and DNA repair.

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Therefore, it is plausible that ATX3, as a DUB, functions to deubiquitinate Chk1 to counteract the action of E3 ligases.

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Our result indicated that GST-ATX3 effectively decreased the polyubiquitination of Chk1 in a dose dependent manner.

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ATXN3 leads to the deubiquitination of VCP. 3 / 3

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We propose that atx3 may promote deubiquitination of p97 bound substrates to facilitate their transfer to the proteasome during retrotranslocation (XREF_FIG).

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Ataxin-3 and YOD1 promote the deubiquitination of p97 associated ERAD substrates, and facilitate delivery to the proteasome [21-24].

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We present evidence that atx3 may promote p97-associated deubiquitination to facilitate the transfer of polypeptides from p97 to the proteasome.

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ATXN3 deubiquitinates HDAC3. 3 / 3

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Moreover, ATXN3 deubiquitinates HDAC3, thereby enhancing HDAC3 protein stability.

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ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3

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Likewise, ATXN3 has been shown to exacerbate type I antiviral response via the deubiquitination and stabilization of histone deacetylase 3 (HDAC3) (Feng et al., 2018).

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ATXN3 deubiquitinates TP53. 3 / 3

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Thus, ATX-3 deubiquitinates and stabilizes p53 (XREF_FIG), which is an essential step for p53 function in cell cycle arrest and apoptosis (XREF_FIG).

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To determine whether ATX-3 can deubiquitinate p53 directly in vitro, we performed in vitro deubiquitination assays.

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ATXN3 deubiquitinates BECN1. 2 / 2

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Ataxin-3 deubiquitinates beclin-1 that then escapes proteasomal destruction and triggers starvation-induced autophagy.

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This interaction allows the deubiquitinase activity of ataxin-3 to protect beclin 1 from proteasome-mediated degradation and thus enables autophagy.

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ATXN3 leads to the deubiquitination of KLF4. 2 / 2

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ATXN3 promotes breast cancer metastasis by deubiquitinating KLF4.

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Thus, ataxin-3 can bind to and deubiquitinate Ub conjugates, leading us to ask, what are the ubiquitinated substrates ataxin-3 acts upon.

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Other Statements

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ATXN3 affects ATXN3

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ATXN3 activates ATXN3.

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ATXN3 activates ATXN3. 10 / 60

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Non pathogenic ataxin-3 has a polyQ stretch less than 40 glutamine repeats, whereas pathogenic ataxin-3 causing SCA3 has that more than 60 glutamine repeats.

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Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3.

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Machado-Joseph disease (MJD), an autosomal dominant type of spinocerebellar degeneration (SCD), is caused by CAG expansions in the MJD1 gene at chromosome 14q32.1 (Kawaguchi et al., 1994).

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SCA3, which is also known as Machado-Joseph disease (MJD), is caused by abnormal polyQ expansion in the deubiquitinase (DUB) ataxin-3.

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SCA3 is caused by a CAG expansion in the ATXN3 gene for the protein ataxin-3 [XREF_BIBR] with a pathologic expansion number from 52 to 86 [XREF_BIBR].

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For instance, the ATXN3 gene usually contains 13-41 CAG repeats [XREF_BIBR]; more than 55 CAG repeats in the ATXN3 gene are pathogenic and can cause spinocerebellar ataxia type 3 (SCA3), which is a condition characterized by progressive problems with movement [XREF_BIBR].

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SCA3 is caused by a polyQ expansion in the carboxy-terminal portion of a cytosolic protein ataxin-3 (Atxn3) and primarily affects dentate and pontine nuclei and substantia nigra.

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SCA3, considered to be the most common dominantly inherited ataxia in the world, is caused by an abnormal CAG expansion in the ATXN3 gene that is normally 12-42 repeats in length, but is expanded to ~ 52-84 repeats in diseased individuals 1.

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SCA3, which is also known as Machado-Joseph disease (MJD), is caused by abnormal polyQ expansion in the deubiquitinase (DUB) ataxin-3 (Costa Mdo and Paulson, 2012; Matos et al., 2011).

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XREF_BIBR SCA1, SCA2, Machado-Joseph or SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by (CAG) n repeat expansions in the ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, TBP, and ATN1 genes, respectively, and all lead to the expansion of a polyglutamine tract in the corresponding proteins.

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Mutated ATXN3 activates ATXN3. 10 / 10

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Mutant ATXN3 activates the pro apoptotic p53 pathway by activating ATM in SCA3.

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Recent studies have reported that depletion of the mutant ATXN3 allele in a SCA3 transgenic mouse brains rescues the molecular phenotypes of SCA3 supporting the hypothesis that mutant ATXN3 elicits toxicity and neuronal dysfunction in SCA3 [XREF_BIBR].

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Mutant ATXN3 induces genomic DNA damage in SCA3.

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Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive.

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While many studies indicate that SCA3 disease is predominantly caused by the mutant ATXN3 protein, SCA3 rCAG exp RNA has also been implicated in SCA3 pathogenesis.

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As expected, the antibody combination 1H9 and MW1 shows a mutant ataxin-3 specific signal in SCA3 transgenic mice, whereas the antibodies 2B7 and MW1 specifically bind to mutant huntingtin in transgenic Huntington mice (XREF_FIG).

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Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion.

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Autophagy also has a role in clearance of other polyglutamine expanded proteins, including mutant ataxin-3 that is causing the spinocerebellar ataxia type 3 (SCA3) [XREF_BIBR].

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Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease is an autosomal dominant neurodegenerative disease and is caused by the mutation of ATXN3 gene that encodes ataxin-3 (Kawaguchi et al., 1[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Mutant ATXN3 activates the DNA damage response pathway in SCA3.

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ATXN3 activates mutated ATXN3. 2 / 2

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Neurons expressing GFP-atx3 84Q S12D show no difference in the number of excitatory glutamatergic synapses (XREF_FIG) and inhibitory postsynaptic terminals (XREF_FIG) compared with GFP-atx3 28Q WT, suggesting that atx3 phosphorylation at S12 rescues the deleterious outcomes of expanded atx3 expression.

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ATXN3 affects cell death

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ATXN3 activates cell death.

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ATXN3 activates cell death. 10 / 27

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Transient expression of full-length expanded ATX3 (Q84) induced intracellular aggregate formation and cell death when compared with cells expressing constructs with normal ATX3 (Q28), as previously demonstrated.

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Here, we report on the potential use of lithium carbonate and coenzyme Q10 (CoQ10) to reduce the cell death caused by the expanded ATX3 in a cultured cell model.

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The truncated form of mutated ataxin-3 causes aggregation and cell death in vitro and in vivo.

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Our observation demonstrated that the degradation of Hsp27 in SK-N-SH cells is not mediated by the proteasome degradation pathway.We have previously shown that expanded ataxin-3 leads to an increased [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture.

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For example, an expansion of the polyglutamine tract of the ataxin-3 protein, the target protein of SCA3, can lead to decreased Bcl-2 expression and enhance cell death via mitochondria dependent apopt[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Previously, it was shown that ataxin-3 is localized in the cytoplasmic compartment of cells and that expression of ataxin-3 with polyglutamine expansions causes cell death XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.

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In fact, some cellular models of MJD show decreased antioxidant enzyme activity and increased mitochondrial mediated cell death via apoptosis.

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Furthermore, although high level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of NIIs in neurones, there is no close correlation between cell death and NIIs [18[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Ikeda et al. 1996 showed that a short fragment of the MJD1 protein containing 79 polyglns (Q79C) but not the full-length protein with the elongated repeat induced apoptotic cell death in COS cells.

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Mutated ATXN3 activates cell death. 6 / 6

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A neuroendocrine dysfunction, not testicular mutant ataxin-3 cleavage fragment or aggregate, causes cell death in testes of transgenic mice.

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The mutant ataxin-3 forms intranuclear inclusions in cultured cells as well as in diseased human brain and also causes cell death in transfected cells.

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Moreover, overexpression of PNKP in these cells blocked ATXN3-Q84-mediated caspase-3 activation (XREF_FIG), suggesting that the loss of PNKP function plays an important role in mutant ATXN3 mediated cell death.

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Coexpression of p21 (waf1/cip1/sdi1), a cyclin-Cdk inhibitor that induced cell cycle arrest in the G (1) phase, also increased the cell death susceptibility produced by the mutant ataxin-3 fragment in BHK-21 cells.

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Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3 mediated cell death.

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In SCA3, full length mutant ATXN3 has been shown to increase mitochondrial mediated cell death in different models.

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ATXN3 inhibits cell death.

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ATXN3 inhibits cell death. 2 / 5

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In our cellular model, full-length expanded ataxin-3 that leads to neurodegenerative disorders significantly impaired the expression of Bcl-2 protein, which may be, at least in part, responsible for the weak tolerance to polyglutamine toxicity at the early stage of disease and ultimately resulted in an increase of stress induced cell death upon apoptotic stress.

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Overexpression of ATXN3 in polyQ neurodegeneration models in Drosophila suppresses toxicity and cell death, implying that ATXN3 is a neuroprotective protein; its neuroprotective action, moreover, depends both on its DUB activity and proper functioning of the proteasome.

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ATXN3 affects TP53

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ATXN3 activates TP53.

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ATXN3 activates TP53. 10 / 17

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When the FL ATX-3 mRNA was injected into WT but not the p53 mutant zebrafish embryos, significantly more apoptotic cells were observed in TUNEL staining assays, indicating that ATX-3 caused p53 dependent apoptosis in vivo.

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Using the zebrafish model system, we further examined whether ATX-3 induces p53 dependent apoptosis in vivo.

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Furthermore, to test whether mutant ATXN3 activates p53 and Chk2 via activating ATM, we pre-treated the cells with ATM inhibitor Ku55933 and expressed ATXN3-Q84 and assessed the activation of DNA damage response pathway.

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Flow cytometry analysis using Annexin V-FITC and propidium iodide (PI) staining in HCT116 cells showed that knockdown of ATX-3 led to a decrease of camptothecin (CPT)-induced apoptosis, while ectopic expression of ATX-3 but not the catalytic inactive mutant ATX-3-C14A resulted in a significant increase of apoptosis in HCT116 p53 +/+ but not HCT116 p53 -/- cells (XREF_FIG), indicating that ATX-3 promoted p53 mediated apoptosis, which required its deubiquitinating enzymatic activity.

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As P53 has known functions in cycle arrest and apoptosis, this indicates that expression of atxn3 polyQ repeats induces selective transcription and expression of p53 target genes and promotes p53 dependent apoptosis in the CNS of zebrafish [XREF_BIBR].

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ATX-3 Promotes p53 Dependent Apoptosis in Cells and in Zebrafish.

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Activation of p53 by mutant ataxin-3 is also related to phosphorylation of p53 at ser15 residue in the SCA3 transgenic mice model.

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Besides, we found that the degradation of p53 in the ATX-3 exp (80Q)-expressing cells was slower than that of normal ATX-3-expressing cells (XREF_SUPPLEMENTARY), and ectopic expression of polyQ expanded ATX-3 induced higher levels of p53 protein than the normal ATX-3 in RKO, 293T, and MEF cells (XREF_SUPPLEMENTARY), indicating that polyQ expanded ATX-3 possessed enhanced capability to stabilize p53.

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These results suggest that ATX-3 deletion inhibits the stimulation of p53 transactivation activity.

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However, the polyQ expanded ATX-3 induced progressive severe p53 dependent neurodegeneration in the central nervous system of zebrafish, suggesting that it caused other kinds of p53 mediated neural cell death besides apoptosis, too.

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Mutated ATXN3 activates TP53. 6 / 6

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Mutant ATXN3 activates the pro apoptotic p53 pathway by activating ATM in SCA3.

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Specific modulation of mutant ATXN3 mediated atypical activation of the DNA damage response p53 and PKCdelta pathways, or enhancing the efficacy of in vivo DNA damage repair may be effective strategies to combat the pathways leading to systemic neurodegeneration in SCA3.

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Knockdown of normal ATXN3 or PNKP, or expression of mutant ATXN3 increased the accumulation of DNA damage and persistent activation of the ATM and p53 dependent DNA repair pathway, suggesting ATXN3 may be a key regulator of PNKP dependent DNA repair.

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Consistent with our hypothesis, ATXN3-Q84 expression failed to stimulate phosphorylation of Chk2 and p53 in the presence of the ATM inhibitor Ku55933 (XREF_SUPPLEMENTARY), substantiating our interpretation that mutant ATXN3 stimulates the DNA damage response p53 pathway via activating ATM.

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Notably, compared with normal ataxin-3 protein, the gain-of-function mutant ataxin-3 triggers higher p53 protein and p53 responsive gene expression and causes more severe p53 dependent neurodegeneration in brain neuron cells of transgenic zebrafish and SCA3 mice 13.

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Modified ATXN3 activates TP53. 1 / 1

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Deletion of ATXN3 resulted in destabilization of p53, whereas ectopic expression of ATXN3 induced expression of p53 target genes and promoted p53-dependent apoptosis.

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ATXN3 inhibits TP53.

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ATXN3 inhibits TP53. 1 / 3

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Mutated ATXN3 decreases the amount of TP53. 1 / 1

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Reducing p53 levels using transgenic RNAi did not alter the toxicity of mutant ataxin 3, as monitored by vacuole formation (XREF_SUPPLEMENTARY), consistent with specificity of the rescue of GFAP toxicity.

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L-glutamine affects ATXN3

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L-glutamine activates ATXN3. 10 / 28

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SCA3 is caused by an expanded polyglutamine tract in the ataxin-3 protein, resulting in conformational changes that lead to toxic gain of function.

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Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3.

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Spinocerebellar ataxia type 3 (SCA3) is caused by an expanded polyglutamine stretch in ataxin-3.

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Hsp104 suppresses polyglutamine induced degeneration post onset in a drosophila MJD and SCA3 model.

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For example, SCA3 is caused by abnormal expansion of the polyglutamine in the C-term region of the protein, and the cleavage of the C-term fragment by caspases has been suggested to be essential for pathology of the disease XREF_BIBR.

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Six of the most frequent dominantly inherited spinocerebellar ataxias (SCAs) worldwide - SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 - are caused by an expansion of a polyglutamine (polyQ) tract in the corresponding proteins.

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Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3), an autosomal dominant neurological disorder, is caused by an abnormal expanded polyglutamine (polyQ) repeat in the ataxin-3 protein.

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Hsp104 Suppresses Polyglutamine Induced Degeneration Post Onset in a Drosophila MJD and SCA3 Model.

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Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is autosomal dominant neurodegenerative disease caused by an expansion of polyglutamine encoding CAG repeats in the ATXN3 gene.

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Spinocerebellar ataxia type 3 (SCA3), the most common spinocerebellar ataxia, is caused by a polyglutamine (polyQ) expansion in the protein ataxin-3 (ATXN3).

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ATXN3 affects CHEK1

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ATXN3 activates CHEK1.

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ATXN3 activates CHEK1. 6 / 14

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Indeed, overexpression of FBXO6 or DDB1 resulted in significant decrease of Chk1 protein level, whereas co-expression of ATX3 effectively restored Chk1 from E3 ligase mediated degradation.

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Taken together, our results demonstrated that ATX3 promoted Chk1 stability through the ubiquitin-proteasome pathway.

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Moreover, ATX3 depleted cells re-entered the cell cycle more rapidly than WT cells did, implying that Chk1 reduction caused by ATX3 knockout can accelerate recovery from the G2/M damage checkpoint, which is consistent with previous results from Chk1-/- ES cells.

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To test if ATX3 may promote Chk1 stabilization, we first evaluated whether ATX3 deficiency impairs Chk1 stability.

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Ataxin-3 promotes genome integrity by stabilizing Chk1.

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As mentioned above, ATX3 promotes Chk1 stability through inhibiting its proteasomal destruction.

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In subsequent experiments, we investigated whether overexpression of ATX3 upregulates the steady-state Chk1 level.

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If ATX3 stabilizes Chk1, then forced expression of ATX3 should upregulate the steady-state level and stability of Chk1.

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Indeed, transient lentiviral expressions of ATX3 in WT and KO cells caused higher levels of Chk1 than control cells transfected with vector.

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ATXN3 decreases the amount of CHEK1.

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Modified ATXN3 decreases the amount of CHEK1. 1 / 1

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Indeed, overexpression of ATX3 but not ATX3-C14A significantly reduced the polyubiquitination level of Chk1 (XREF_SUPPLEMENTARY).

28180282

ATXN3 affects PNKP

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ATXN3 inhibits PNKP.

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ATXN3 inhibits PNKP. 6 / 8

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Diminished PNKP activity results in persistent accumulation of DNA strand breaks, leading to chronic activation of the DNA damage response ataxia telangiectasia mutated (ATM) protein kinase and the downstream pro apoptotic p53 dependent signaling pathways in SCA3.

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Recently, two research teams reported the interaction between ATX3 and PNKP, and discovered that polyQ expanded ATX3 inactivates PNKP phosphatase activity, causing persistent DNA damage and chronic activation of pro apoptotic signaling, which leads to SCA3 pathogenesis.

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Hence, PNKP inactivation by expanded ataxin-3 may serve an important role in SCA3 pathogenesis, especially given the fact that the nervous system is particularly sensitive to DNA damage compared to other tissues xref .

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It has been suggested that the PNKP inactivation by mutant ataxin-3 might in part be explained by its recruitment in polyQ aggregates xref .

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We have shown previously that ATXN3 depleted or pathogenic ATXN3 expressing cells abrogate polynucleotide kinase 3 '-phosphatase (PNKP) activity.

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It has been suggested that the PNKP inactivation by mutant ataxin-3 might in part be explained by its recruitment in polyQ aggregates XREF_BIBR.

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Mutant ATXN3 has also been found to sequester PNKP outside the nucleus and thereby impair its ability to take part in DNA repair [XREF_BIBR].

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Conversely, polyQ expanded mutant ATXN3 inhibited PNKP activity, possibly as a result of PNKP sequestration into ATXN3 aggregates.

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The wild-type ATXN3 protein stimulated, and in contrast, the mutant ATXN3 dramatically diminished, the 3 ' phosphatase activity of PNKP in vitro (Chatterjee et al; Figs.

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In conclusion, our current study provides compelling evidence of how mutant ATXN3 impedes the enzymatic activity of PNKP, and induces DNA damage that manifests with activation of the pro apoptotic signaling pathways in SCA3.

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Here we report that WT ATXN3 stimulates, and by contrast mutant ATXN3 blocks the DNA 3 '-end-processing activity of PNKP, and the resulting accumulation of DNA SBs may contribute significantly to SCA3 pathogenesis via modulating the DNA damage response pathway.

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These data further support the idea that the mutant ATXN3 specifically blocks the activity of PNKP, but not that of DNA polymerase or ligase (XREF_SUPPLEMENTARY).

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ATXN3 activates PNKP.

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ATXN3 activates PNKP. 6 / 10

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Two studies in 2015 showed that ATXN3 binds to and enhances PNKP 3 '-phosphatase activity, promoting DNA repair.

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Our studies described in the accompanying manuscript by Chatterjee et al suggest that PNKP is a native ATXN3 interacting protein, and that ATXN3 modulates PNKP activity and DNA repair (Chatterjee et al, Figs.

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However , how ATXN3 enhances PNKP activity was not clear from these studies .

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However, how ATXN3 enhances PNKP activity was not clear from these studies.

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XREF_FIG shows that WT ATXN3 stimulated PNKP 's 3 '-phosphatase activity (ln 2 vs. lns 3-7) ~ 4-fold; in contrast, ATXN3-Q72 reproducibly and significantly abrogated PNKP 's activity (~ 3.5-fold, XREF_FIG, ln 2 vs. ln 6; n = 3).

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Interestingly, it was shown that wild-type ataxin-3 led to stimulation of PNKP, whereas expanded ataxin-3 led to inhibition XREF_BIBR XREF_BIBR.

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VCP affects ATXN3

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VCP activates ATXN3.

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VCP activates ATXN3. 10 / 21

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We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity.

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Nevertheless, we sought to investigate whether VCP and p97 similarly stimulated the protease activity of expanded ataxin-3.

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An arginine and lysine rich motif is crucial for VCP and p97 mediated modulation of ataxin-3 fibrillogenesis.

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Here, we sought to investigate whether VCP and p97 or hHR23A, both of which are involved in protein degradation pathways, also enhanced ataxin-3 activity through direct interactions.

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VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex.

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The 282 RKRR-HNHH substitution disrupts the interaction of VCP and p97 with wild-type and expanded ataxin-3, and blocks VCP and p97 activation of ataxin-3 DUB activity.

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The same study also showed that recombinant VCP stimulates fibrillogenesis and aggregation of recombinant, pathogenic ataxin-3 in a dose dependent manner in reconstituted systems, but only up to a point; molar excess VCP suppresses ataxin-3 fibrillogenesis.

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Valosin Containing Protein (VCP and p97) Is an Activator of Wild-Type Ataxin-3.

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This result validates the direct VCP stimulation of wild-type ataxin-3.

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VCP and p97 does not enhance ubiquitin hydrolase activity of expanded ataxin-3.

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VCP inhibits ATXN3.

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VCP inhibits ATXN3. 2 / 2

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Nevertheless, interaction with hHR23A could change the affinity of ataxin-3 for VCP and p97 and thus impair VCP and p97 induced activation of ataxin-3.

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ATXN3 affects Ubiquitin

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ATXN3 inhibits Ubiquitin.

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ATXN3 inhibits Ubiquitin. 10 / 11

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Together, these results indicate that ataxin-3 functions with CHIP to prevent the incorporation of additional ubiquitin to chains on substrates once they reach a certain length.

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Thus, in one possible mechanism of suppression, ataxin-3 could suppress toxicity by simply increasing the pool of free ubiquitin.

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For instance, the deubiquitinase Ataxin-3 was shown to interact with C-terminus of Hsc70 Interacting Protein (CHIP), a major mammalian E3 ligase involved in cytosolic PQC, to limit the length of ubiquitin chains built on CHIP substrates XREF_BIBR.

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By binding the minimum length poly-ubiquitin chain on substrates, ATXN3 may prevent complete removal of the ubiquitin chain by other DUBs, and thus facilitate its recognition by the 26S proteasome.

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PolyQ expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin.

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Absence of ataxin-3 UIMs 1 and 2 shows reduced binding of ubiquitin chains.

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An unbiased, semi-automated quantitative analysis (XREF_SUPPLEMENTARY) revealed that knock-down of ataxin-3 indeed impaired the accumulation ofRNF8 (Fig XREF_FIG A), RNF168 (Fig XREF_FIG B), and ubiquitin conjugates atlaser induced DSBs (Fig XREF_FIG C).

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In CHIP ubiquitination assays, ataxin-3 functions to restrict the length of ubiquitin chains attached to CHIP substrates, terminating ubiquitin incorporation once chains reach a critical length.

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We have found that aggregation of polyQ expanded Atx3 can sequester P97 and Ub conjugates into the protein aggregates or inclusions through specific interactions both in vitro and in cells.

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These results support a model in which ataxin-3 effectively limits ubiquitin chain extension once chains reach a critical length.

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ATXN3 activates Ubiquitin.

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ATXN3 activates Ubiquitin. 6 / 7

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Whether ataxin 3 produces unanchored ubiquitin chains and activates HDAC6 remains to be tested.

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Mono-ubiquitination of ataxin-3, which is enhanced by proteotoxic stress, increases its ubiquitin hydrolase activity XREF_BIBR.

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As reported previously, ataxin-3 (Q22) deubiquitinates K63 linked ubiquitin chains and promotes the appearance of smaller ubiquitin chains over time.

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Through this process, ataxin-3 can facilitate substrate entry into the proteasome, as well as mediate other ubiquitin dependent pathways.

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Ataxin-3 containing the 71Q expansion associated with RNF8 mediated ubiquitin chains with similar efficiency as wild-type ataxin-3 (10Q), indicating that the expanded polyQ stretch does not affect the ubiquitin binding activity of ataxin-3.

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CHIP associated Ataxin-3 promotes the efficacy of Ub labeling on CHIP substrates, probably by preventing the lengthy Ub chain extension on CHIP substrates.

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ATXN3 increases the amount of Ubiquitin.

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ATXN3 increases the amount of Ubiquitin. 1 / 1

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With anti-Ubi N antibody, we show that altering ataxin-3 levels did not affect the levels of ubiquitin moieties expressed in cells (XREF_FIG F, comparing input lanes 1 and 7, and lanes 4 and 10) or pulled down in the aggregates (XREF_FIG F, comparing lanes 3 and 9 and lanes 6 and 12), suggesting that ataxin-3 knockdown did not reduce the total level of ubiquitin expressed in cells or the ubiquitin associated with protein aggregates but only specifically reduced the amount of unanchored ubiquitin C termini in protein aggregates.

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STUB1 affects ATXN3

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STUB1 activates ATXN3.

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STUB1 activates ATXN3. 8 / 8

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It was previously reported that overexpression of CHIP increases the ubiquitination and degradation rates of polyQ expanded Atx3, which is also enhanced by HSP70 XREF_BIBR.

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It was recently shown that CHIP promotes the degradation of polyQ expanded ataxin-3 and, together with Hsc70 protein, suppresses the aggregation and cytotoxicity mediated by huntingtin (Jana et al., 2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The possibility of redundancy in E3 ligase action is suggested by reports that overexpression of either CHIP or Parkin increases ubiquitination of polyglutamine expanded ataxin-3 and reduces its cellular toxicity.

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Although in this case, the E3 ligases that are acting redundantly to CHIP have not been identified, overexpression of either CHIP or parkin promotes the degradation of nNOS and polyglutamine expanded ataxin-3.

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However, further analysis revealed certain discrepancies in the CHIP 's effects on different polyQ proteins; for example, CHIP increases the degradation of polyQ expanded ataxin-3 while it does not af[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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XREF_FIG - XREF_FIG demonstrate that CHIP promotes degradation of two signaling proteins, GR and nNOS, and two poly Q expanded proteins, AR112Q and Q78 ataxin-3.

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Our findings and recent reports lead us to favor a model in which mono-ubiquitination of CHIP promotes recruitment of ataxin-3 to the complex before chain formation on substrates.

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Transient overexpression of CHIP increases the ubiquitination and the rate of degradation of polyglutamine expanded huntingtin or ataxin-3.

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Modified STUB1 activates ATXN3. 1 / 1

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In cell models of HD and MJD, CHIP overexpression promoted ubiquitination and degradation of the polyglutamine expanded proteins huntingtin and ataxin-3, and suppressed their aggregation as well as cell death [XREF_BIBR].

20131003

STUB1 inhibits ATXN3.

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STUB1 inhibits ATXN3. 7 / 7

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CHIP has also been shown to degrade Ataxin-3 [ 59 ] .

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CHIP has also been shown to degrade Ataxin-3 [XREF_BIBR].

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Additionally, reduction in CHIP expression enhances expanded ataxin-3 toxicity in vivo.

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Interestingly, when expanded ataxin-3 was present, CHIP levels were also reduced in the brains of MJD transgenic mice, raising the possibility that loss of one or both E3 partners may be a contributing factor in the pathogenesis of SCA3.

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In contrast to ataxin-1, CHIP indeed promoted the degradation of polyQ expanded ataxin-3 (73Q) without causing its accumulation in the insoluble fraction, especially at the highest concentration.

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In parallel, CHIP reduction markedly increases the level of ataxin-3 microaggregates, which partition in the soluble fraction of brain lysates yet are resistant to dissociation with denaturing detergent, and which precede the appearance of inclusions.

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The dose dependent phenotype caused by CHIP reduction in Q71-B mice allowed us to determine whether CHIP reduction enhances ataxin-3 aggregation and to correlate biochemically detectable changes in aggregation to behavioral phenotype.

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STUB1 decreases the amount of ATXN3.

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STUB1 decreases the amount of ATXN3. 3 / 3

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For example, overexpression of the human TPR domain-containing co- chaperone CHIP suppresses neurodegeneration in fly models expressing polyQ-containing versions of ataxin 1 and the N-terminal huntingtin fragment (Al-Ramahi et al., 2006).

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As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level.

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Also, consistent with effects in non neuronal cells, both CHIP and Parkin decreased Q78 ataxin-3 levels in MN-1 neuronal cells but Mdm2 did not (XREF_FIG).

18784277

ATXN3 affects PRKN

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ATXN3 activates PRKN.

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ATXN3 activates PRKN. 7 / 7

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As mutant, but not wild-type ataxin-3 promotes clearance of parkin via the autophagy pathway, there seems to be a possibility that increased turnover of parkin contributes to pathogenesis in MJD.

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Hence, it is likely that ataxin-3 edits ubiquitin chains to target Parkin to different cellular pathways such as DNA repair and autophagy (see Section 3).

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In MJD, these partnership are not only disrupted, but the presence of the expanded ataxin-3 now promotes clearance of both parkin and CHIP, which over time can have deleterious consequences on neurons in MJD and PD.

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Moreover, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of the Parkinsonian features in MJD.

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Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway.

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Supporting the notion that polyglutamine expansions alter ataxin-3 function, it was recently reported that pathogenic ataxin-3 targets the E3 ligase parkin for autophagic degradation, unlike wild-type ataxin-3, which rescues it through deubiquitination [XREF_BIBR].

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These findings were further confirmed and extended in cells, with the presence of the expanded form of ataxin-3 promoting clearance of parkin through the autophagy pathway.

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Mutated ATXN3 activates PRKN. 1 / 1

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Given that the loss of parkin function leads to PD, we propose that the increased turnover of parkin triggered by mutant ataxin-3 may explain some of the parkinsonian features observed in MJD.

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ATXN3 inhibits PRKN.

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ATXN3 inhibits PRKN. 4 / 5

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For example, mutant ataxin-3, the causative protein abnormality in SCA3, has been shown to enhance the autophagic degradation of parkin, which may in turn explain some of the parkinsonian features seen in this condition [XREF_BIBR].

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63 Interestingly, PolyQ expanded Ataxin-3 promotes degradation of Parkin via autophagy, 64 which helps explain why Parkin protein levels are decreased in the brain of transgenic mice overexpressing polyQ expanded but not wild type Ataxin-3.

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We reported that the mutant form of ataxin-3, the protein responsible for MJD, promotes the autophagic degradation of parkin.

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However, the MJF associated form of ataxin-3 promotes Parkin degradation in a proteasome independent manner [XREF_BIBR, XREF_BIBR].

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Mutated ATXN3 inhibits PRKN. 2 / 2

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ATXN3 activates HSPA.

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ATXN3 activates HSPA. 10 / 13

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We note that, despite gross similarity, SCA3 degeneration is not identical to general misfolding : some suppressors of Ataxin-3 toxicity strikingly enhanced dominant negative Hsp70 (upregulation of DnaJ-1 and Tpr2), whereas the enhancer CG11033 E3093 suppressed it.

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Atxn3 increased hsp70 basal promoter activity and this may be responsible for some of the enhanced stress induced promoter activity; however, Atxn3 may modulate stress induced activity through other mechanisms.

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Although Atxn3 regulated hsp70 basal promoter activity and protein, it was unexpected that Atxn3 also modulated stress induced hsp70 promoter activity and protein following heat shock and AZE stresses.

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To determine if Atxn3 modulation of hsp70 promoter activity extended beyond basal activity, WT and KO cells were treated with stressors that induce hsp70 (heat shock, cadmium, and AZE), as well as a stressor that typically does not induce hsp70, 2-DG.

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Hsp70 regulation and its functions are critical for cellular homeostasis; therefore, we examined the possibility that Atxn3 modulates hsp70.

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Transfecting ataxin-3 restored hsp70 basal promoter activity in KO fibroblasts to levels of promoter activity in WT cells; however, mutations that inactivated deubiquitinase activity or the ubiquitin interacting motifs did not restore full activity to hsp70 basal promoter activity.

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Under basal conditions (0 time), transfected Atxn3 increased basal activity of the hsp70 promoter as previously shown in Fig.

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This suggested that Atxn3 modulated stress induced hsp70 promoter activity in response to these stresses.

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ATX-3 Promotes p53 Dependent Apoptosis in Cells and in Zebrafish.

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SUMOylation did not influence the subcellular localization, ubiquitination or aggregates formation of mutant-type ataxin-3, but partially increased its stability and the apoptosis rate of the cells.

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SUMOylation did not influence the subcellular localization, ubiquitination or aggregates formation of mutant-type ataxin-3, but partially increased its stability and the cell apoptosis.

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In addition, ATXN3 SUMOylation by SUMO-1 on site K166 also increases apoptosis in SCA3; therefore, SUMOylation by SUMO-1 might stimulate SCA3 pathogenesis through both effects described above.

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| PMC

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Using the zebrafish model system, we further examined whether ATX-3 induces p53 dependent apoptosis in vivo.

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These workers have also shown that overexpression of the MJD protein with expanded polyglutamine repeats leads to apoptosis, both in vitro and in vivo.

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In a SCA 3 cell model, the expression of a fragment of ataxin-3 containing an elongated polyQ stretch induced apoptosis and cell death as well as a severe ataxia in a mouse model, showing a more rapid manifestation of a SCA 3-reminiscent phenotype when compared to mice expressing full length mutant ataxin-3 [XREF_BIBR].

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Modified ATXN3 activates apoptotic process. 1 / 1

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Deletion of ATXN3 resulted in destabilization of p53, whereas ectopic expression of ATXN3 induced expression of p53 target genes and promoted p53-dependent apoptosis.

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Mutated ATXN3 activates apoptotic process. 1 / 1

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Inactivation of PNKP by Mutant ATXN3 Triggers Apoptosis by Activating the DNA Damage Response Pathway in SCA3.

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ATXN3 inhibits apoptotic process.

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ATXN3 inhibits apoptotic process. 1 / 1

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ATXN3 affects L-glutamine

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ATXN3 activates L-glutamine.

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ATXN3 activates L-glutamine. 8 / 8

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Spinocerebellar ataxia type 3 (SCA3) is a human polyglutamine disease caused by mutations in the gene encoding Ataxin-3, resulting in progressive dysfunction of the cerebellum [XREF_BIBR].

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The NIs in our cases are consistently labeled for ataxin-3, yet genetic screening failed to reveal expanded CAG repeats in ataxin-3 or other diseases causing polyglutamine containing proteins.

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The pathology of spinocerebellar ataxia type 3, also known as Machado-Joseph disease, is triggered by aggregation of toxic ataxin-3 (ATXN3) variants containing expanded polyglutamine repeats.

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Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is a polyglutamine (polyQ) neurodegenerative disorder caused by abnormal (more than 40 repeats) CAG nucleotide repeat expansions in the ataxin-3 (ATXN3) gene, which encodes a protein that is involved in ubiquitin-proteasome system degradation of proteins [XREF_BIBR, XREF_BIBR].

| PMC

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Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3.

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SCA3 is caused by an expansion mutation of cytosine-adenine-guanine (CAG) repeats encoding a polyglutamine stretch from 51 to 91 repeats in the ataxin-3 gene, which normally has fewer than 44 CAG repeats.

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We have previously shown that rapamycin attenuates the phenotype in a mouse model of Huntington disease when administered pre-symptomatically and have recently extended this to demonstrate the effectiveness of rapamycin in a transgenic mouse model of spinocerebellar ataxia type 3, a polyglutamine disorder caused by mutations in the ataxin-3 gene.

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SCA3 is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormally long polyglutamine stretch in the encoded ATXN3 protein.

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ATXN3 inhibits L-glutamine.

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ATXN3 inhibits L-glutamine. 7 / 7

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Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin associated mechanism.

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In contrast, full-length expanded ataxin-3 with an even longer repeat caused a much milder, selectively neurotoxic phenotype, and normal ataxin-3 actually suppressed the toxicity of other polyglutamine disease proteins.

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Strikingly, it was found that ATXN3 suppresses polyglutamine neurodegeneration in Drosophila, and this suppressing activity is dependent on its interaction with ubiquitin and on its protease activity [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Like CHIP, ataxin-3 suppresses polyglutamine toxicity and does so in a manner linked to its ubiquitin associated activities.

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Exogenous expression of human wild-type ataxin-3 in Drosophila suppressed polyglutamine related neurodegeneration in vivo, in a manner that was dependent on its Ub binding and chain cleaving properties [XREF_BIBR].

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Parkin can also target polyglutamine proteins ataxin-2 and ataxin-3 for ubiquitination to negatively control their levels and reduce these polyglutamine proteins induced cytotoxicity [XREF_BIBR, XREF_BIBR].

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In Drosophila, ataxin-3 suppresses the toxicity of expanded polyglutamine proteins in a manner that requires the catalytic activity of the Josephin domain XREF_BIBR.

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ATXN3 affects autophagy

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ATXN3 activates autophagy.

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ATXN3 activates autophagy. 10 / 11

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Paradoxically, in a fly model of SCA3 (another polyQ disease), flies expressing pathogenic SCA3 (SCA3trQ78) display increased autophagy and neurodegenerative phenotypes, indicating that increased autophagy may promote the disease.

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While Ataxin-3 deficient cells are still able to induce autophagy, the induction process appeared to be exaggerated with an increased number of autophagosomes, which is accompanied by less efficient turnover of proteins by autophagy.

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No change in the number of LC3-II vesicles was observed when the Q35 tract was expressed in beclin 1 depleted cells (XREF_FIG) and the inhibitory effect of Q35 on beclin 1 levels and autophagy in beclin 1 expressing cells was rescued by ataxin-3 overexpression (XREF_FIG), compatible with the model that the Q35 acts by impairing ataxin-3 control of beclin 1 levels.

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Furthermore, pathogenic ATXN3 induces autophagy in a Drosophila model.

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The normal function of Ataxin-3 is in ubiquitin modulated pathways [XREF_BIBR - XREF_BIBR]; our data suggest the possibility that Ataxin-3 may also modulate autophagy.

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First, we determined whether normal or pathogenic Ataxin-3 itself induced lysosomal accumulation reflective of autophagy, by examining the fat body tissue from larvae, a standard assay for autophagy [XREF_BIBR].

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This may arise from beclin-1 degradation caused by expanded mutant ataxin-3 polyQ , whereas normal ataxin-3 promotes autophagy by preventing proteosome degradation of beclin-1 [ 77,78 ] .

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Interestingly, early studies indicated that proteins containing PolyQ, for example, Ataxin-3, might interact with Beclin 1 to promote the autophagy [XREF_BIBR], and AR proteins with different PolyQ lengths have been reported to have different transactivation capacity to modulate AR target genes [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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Since autophagy can mediate the clearance of polyQ expanded ataxin-3, we presumed that the over-expression of ataxin-3 alone is sufficient to induce autophagy.

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An independent study described a similar induction of autophagy by Ataxin-3 in Drosophila, suggesting that induction of autophagy by pathogenic aggregates is a common phenomenon in neurodegenerative diseases [XREF_BIBR].

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ATXN3 bound to GABARAP activates autophagy. 1 / 1

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The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C and GABARAP and promotes autophagy.

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Mutated ATXN3 activates autophagy. 1 / 1

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Enhanced autophagy decreases the toxic accumulation of these mutant proteins, such as mutant huntingtin (Huntington 's disease), mutant alpha synuclein (Parkinson 's disease), mutant ataxin-3 (spinocerebellar ataxia type 3) and tau.

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ATXN3 inhibits autophagy.

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Mutated ATXN3 inhibits autophagy. 1 / 1

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Figure 2 (based on [2, 67]) shows how an expansion of the polyQ repeat in mutant ataxin-3, as well as excess polyQ from other cellular (or viral) proteins, could interfere with the interaction of ataxin-3 and beclin-1 to inhibit autophagy.

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CAPN affects ATXN3

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CAPN activates ATXN3.

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CAPN activates ATXN3. 10 / 12

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This phenotype could be abolished by calpain inhibition, indicating a key role of calpain in ATXN3 aggregation.

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Calpain inhibition is sufficient to suppress aggregation of polyglutamine expanded ataxin-3.

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Calpain mediated cleavage of ataxin-3 has an important role in SCA3 pathogenesis [XREF_BIBR].

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Calpain cleavage sites have been identified along the ataxin-3 protein, supporting the hypothesis of calpain mediated ataxin-3 proteolysis.

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Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease.

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It was discovered that inhibition of Ca 2+ -dependent protease calpain suppressed aggregation of polyglutamine expanded Atxn3 in transfected cells [XREF_BIBR].

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It was discovered that inhibition of Ca 2+ -dependent protease calpain suppressed aggregation of polyglutamine expanded Atxn3 in transfected cells.

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It was discovered that inhibition of Ca 2+ -dependent protease calpain suppressed aggregation of polyglutamine expanded Atxn3 in transfected cells [XREF_BIBR].

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Calpain mediated ataxin-3 cleavage has also been proposed to be the determinant of neuronal specificity of pathology in SCA3.

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Based on observed fragment sizes and antibody binding, calpain mediated cleavage of ataxin-3 has been shown to occur most convincingly at amino acid 60, 221, and 260 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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CAPN increases the amount of ATXN3.

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CAPN increases the amount of ATXN3. 1 / 1

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In an MJD zebrafish model, calpain inhibition reduced polyQ expanded ataxin-3 levels in an autophagy dependent manner [XREF_BIBR].

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ATXN2 affects ATXN3

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ATXN2 activates ATXN3.

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ATXN2 activates ATXN3. 10 / 11

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At the 24-h time point, coexpression of normal Atx2 with pathogenic Atx3 caused the early appearance of SDS-insoluble Atx3 complexes that remain within the stacking gel (compare lanes 1 and 2), presumably reflecting protein accumulations that correlate with the early appearance of nuclear inclusions in cryosections.

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Atx-2 was found to mediate the pathogenic effects of SCA-1 and SCA-3.

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Up-regulation of atx2 synergistically enhanced SCA3 degeneration, and strikingly, we found that the endogenous activity of atx2 modulates progression of neurodegeneration induced by pathogenic Atx3.

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These observations indicated that PABP has the opposite activity as Atx2 with respect to Atx3 dependent neurodegeneration : whereas Atx2 enhances the toxicity of Atx3, PABP is protective.

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In the fly, endogenous Atx2 colocalized with pathogenic Atx3 in inclusions, as seen in human patients [XREF_BIBR], with up-regulation of Atx2 enhancing Atx3 toxicity concomitant with a faster onset of inclusions and of SDS-insoluble complexes.

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Ataxin gene variants in ATXN1, ATXN2, ATXN3, and ATXN7 cause SCA1, SCA2, SCA3, and SCA7, respectively.

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Up-Regulation of Atx2 Synergistically Enhances Atx3 Induced Neurodegeneration.

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Moreover, up-regulation of atx2, the Drosophila ortholog of the human gene that causes SCA2 disease, has been shown to enhance the toxicity of human disease forms of SCA1 and SCA3 in flies [XREF_BIBR].

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SCA2 and SCA3 are caused by polyglutamine expansions in ataxin2 and ataxin3, respectively [XREF_BIBR, XREF_BIBR].

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ATXN2 inhibits ATXN3.

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ATXN2 inhibits mutated ATXN3. 2 / 2

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Re-establishment of ataxin-2 levels reduces mutant ataxin-3 and alleviates Machado-Joseph disease pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyQ disorders.

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Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado-Joseph disease.

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ATXN3 affects DNA damage checkpoint

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ATXN3 activates DNA damage checkpoint.

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Mutated ATXN3 activates DNA damage checkpoint. 10 / 10

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XREF_FIG), suggesting that mutant ATXN3 strongly activates the DNA damage response pathway and the polyQ sequence length is important for ATM pathway activation.

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, suggesting that the mutant ATXN3 induced DNA damage response ATM pathway activation is oxidation independent.

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The amelioration of apoptosis by pharmacological inhibition of ATM and p53, suggest that mutant ATXN3 mediated aberrant activation of the DNA damage response pathway facilitates the apoptotic demise of neuronal cells in SCA3.

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Either overexpression of PNKP or pharmacological inhibition of ATM in mutant ATXN3 expressing cells blocked aberrant activation of the pro death pathways and reduced cell death, suggesting that mutant ATXN3 mediated chronic activation of the DNA damage response ATM signaling pathway plays a pivotal role in neuronal dysfunction and neurodegeneration in SCA3.

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Likewise, expression of the mutant ATXN3 carrying 72 and 80 poly-glutamines (ATXN3-Q72 and ATXN3-Q80) in SH-SY5Y cells also strongly activated the DNA damage response ATM pathway (XREF_SUPPLEMENTARY).

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XREF_FIG), suggesting that mutant ATXN3 strongly activates the DNA damage response pathway in vivo.

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Mutant ATXN3 activates the DNA damage response pathway in SCA3.

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However, pre-treating cells with NAC did not block mutant ATXN3 mediated activation of the DNA damage response pathway (XREF_SUPPLEMENTARY Figs.)

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ATXN3 activates DNA damage checkpoint. 1 / 1

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In conclusion, as a consequence of the reduced Chk1 protein level, and therefore activity, ATX3 deficiency compromises Chk1 mediated G2/M DNA damage checkpoint.

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ATXN3 inhibits DNA damage checkpoint. 2 / 2

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Therefore, we conclude from these experiments that ATX3 deficiency impairs DNA damage response through regulating Chk1 specifically.

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ATX3 deficiency impairs Chk1 mediated G2/M DNA damage checkpoint.

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PRKN affects ATXN3

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PRKN activates ATXN3.

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Our results raise the possibility that parkin mediated K63 linked polyubiquitination may function upstream of ataxin-3 during aggresome formation.

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Parkin also promotes ubiquitination and degradation of a polyglutamine expanded ataxin-3 and reduces its cellular toxicity [XREF_BIBR, XREF_BIBR].

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Parkin selectively associates with and promotes the ubiquitylation and degradation of polyQ expanded GFP-polyQ fusion protein or ataxin-3 in vivo and in vitro.

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Modified PRKN activates ATXN3. 1 / 1

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PRKN inhibits ATXN3.

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PRKN inhibits ATXN3. 2 / 3

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Overexpression of parkin reduces aggregation and cytotoxicity of an expanded polyglutamine ataxin-3 fragment.

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Similarly, overexpression of the E3 ubiquitin ligase parkin induces ataxin-3 degradation and reduces aggregation and toxicity.

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PRKN inhibits mutated ATXN3. 1 / 1

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Thus, Parkin has been shown to suppress the toxicity of PAEL-R, mutated alpha-synuclein A30P, and a poly (Q)-expanded mutant of ataxin-3.

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PRKN decreases the amount of ATXN3.

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PRKN decreases the amount of ATXN3. 2 / 2

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Parkin lowered the levels of nNOS and Q78 ataxin-3 but did not affect GR or AR112Q, suggesting that it acts redundantly to CHIP on some substrates.

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Also, consistent with effects in non neuronal cells, both CHIP and Parkin decreased Q78 ataxin-3 levels in MN-1 neuronal cells but Mdm2 did not (XREF_FIG).

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Taken together, this study provides evidence showing that the truncated ATXN3 accelerates the formation of aggregates, disrupts the dynamics of mitochondria, and leads to neuronal death in vitro and in vivo.

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It is caused by a CAG over repetition in ATXN3 gene, which translates into a mutated ataxin- 3 protein that accumulates in neurons, causing neuronal dysfunction and death.

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Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications.

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These data supported an idea that, due to enhanced interaction to p53 and up-regulation of p53, polyQ expanded ATX-3 led to an increased p53 dependent neuronal cell death (including both early apoptotic and late apoptotic and necrotic manner).

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The above results indicate that the expanded polyQ tract in ataxin3 could change the DNA methylation status of a variety of genes involved in various biological processes and, thus, cause neuronal death in the cerebellum and spinal cord due to alterations in the expression of these genes.

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In addition, they found that expanded ataxin3 could activate the mitochondrial apoptotic pathway and induce neuronal death by regulating gene expression [XREF_BIBR].

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Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death.

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Mutated ATXN3 activates Death. 4 / 4

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Since the mechanism by which mutant ataxin-3 eventually leads to neuronal death is poorly understood, additional investigations to clarify the biological alterations related to Machado-Joseph disease are necessary.

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These data substantiate our previous interpretation that mutant ATXN3 activates the p53 dependent pro death pathway by activating ATM, and that chronic activation of the ATM --> p53 pathway plays a pivotal role in mediating neuronal death in SCA3.

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Moreover, amelioration of ATXN3-Q84-mediated phosphorylation of p53, c-Abl and PKCdelta by pharmacological inhibition of ATM suggests that mutant ATXN3 activates the pro death signaling cascades via activating ATM in SCA3.

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The susceptibility to death induced by the expression of mutant ataxin-3 varies among individual cell types, even among neurons [14].

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ATXN3 affects ATM

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Mutated ATXN3 activates ATM. 9 / 9

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Since oxidative stress alone can activate the ATM pathway [XREF_BIBR], we sought to determine whether mutant ATXN3 activates ATM via an oxidation dependent mechanism.

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Consistent with these reports, our data show that mutant ATXN3 mediated activation of ATM --> c-Abl pathway enhanced the phosphorylation and facilitated the nuclear translocation of PKCdelta in cells, and in SCA3 transgenic mouse brains.

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Mutant ATXN3 activates the pro apoptotic p53 pathway by activating ATM in SCA3.

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Our data suggest that in addition to activating the DNA damage induced p53 pathway as described earlier in SCA3 [XREF_BIBR, XREF_BIBR], mutant ATXN3 also activates the ATM dependent cAbl --> PKCdelta pro apoptotic pathway in parallel to cause neuronal dysfunction and eventually facilitating systemic neuronal degeneration in SCA3 brain (XREF_FIG).

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Our accompanying manuscript clearly shows that either PNKP depletion or the expression of mutant ATXN3 leads to ATM mediated activation of two parallel proapoptotic pathways; one is p53- and the other c-Abl --> PKCdelta mediated apoptotic cell death, a hallmark of neuropathogenesis (Gao et al..

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To investigate whether mutant ATXN3 activates ATM signaling in SCA3, we expressed ATXN3-Q84 in differentiated SH-SY5Y cells and assessed activation of the ATM pathway.

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ATXN3 activates ATM. 3 / 3

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We also found that ATXN3 and eukaryotic translation initiation factor 5A2 (EIF5A2) protein levels in ATC tissues are positively correlated, and ATXN3 promotes the proliferation and metastasis of ATC cells through EIF5A2.

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Since oxidative stress alone can activate the ATM pathway [ xref ], we sought to determine whether mutant ATXN3 activates ATM via an oxidation-dependent mechanism.

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Moreover, various gain/loss functional assays were performed to indicate that ATXN3 overexpression enhanced ATC cell proliferation and metastasis.

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Valproic acid affects ATXN3

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Valproic acid decreases the amount of ATXN3.

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Valproic acid decreases the amount of ATXN3. 6 / 6

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Valproic acid inhibits ATXN3.

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Another HDAC inhibitor, valproic acid (VPA), produces similar results in Drosophila and SCA3 cell models.

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VPA suppresses apoptosis in SCA3 cell culture model.

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Another HDAC inhibitor, valproic acid (VPA), produces similar results in Drosophila and SCA3 cell models.

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Valproic acid inhibits mutated ATXN3. 2 / 2

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VPA does not inhibit mutant ataxin-3 protein aggregation.

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To rule out the possibility that VPA treatment reduced the amount of nuclear localized mutant ataxin-3 protein aggregations in vitro, we used GFP fluorescence techniques to analyze the proportion of ataxin-3 aggregate- positive cells in ataxin-3-expressing cells at different doses of VPA intervention.

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Valproic acid activates ATXN3.

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XREF_BIBR reported that VPA enhances CREB dependent transcriptional activation in PC12 cell models of MJD.

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ATXN3 affects DNAJB1

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ATXN3 increases the amount of DNAJB1.

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ATXN3 increases the amount of DNAJB1. 5 / 5

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When we conducted quantitative RT-PCR from fly heads that express polyQ78 in their eyes, we found that wild-type ataxin-3 increases the transcription levels of DnaJ-1 (XREF_FIG).

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These findings lead us to propose that ataxin-3, through its interaction with Rad23 and in a manner that depends on its deubiquitinase activity, leads to higher DnaJ-1 protein levels by increasing its transcription.

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When we conducted quantitative RT-PCR from fly heads that express polyQ78 in their eyes, we found that wild-type ataxin-3 increases the transcription levels of DnaJ-1.

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Altogether, our results propose a model whereby ataxin-3 increases DnaJ-1 levels in a manner that depends on the catalytic activity of this DUB and on its interaction with Rad23, and that DnaJ-1, acti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Expression of expanded ataxin-3 on all CHIP backgrounds does not increase Hsp90 or Hsp40 above wild-type levels (XREF_FIG), suggesting no major imbalance in these key chaperones.

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ATXN3 affects transcription, DNA-templated

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ATXN3 inhibits transcription, DNA-templated.

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ATXN3 inhibits transcription, DNA-templated. 9 / 9

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Ataxin-3 is thought to repress transcription via histone dependent chromatin remodeling [XREF_BIBR, XREF_BIBR], and huntingtin modulates the expression of NRSE controlled genes [XREF_BIBR].

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Since expanded ATX3 may disrupt normal gene transcription patterns, lithium may act as a protective factor by modulating gene expression.

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50 Interestingly, ATXN3 has been reported to repress transcription through recruitment of HDAC3 to target promoters 38 or by inhibiting a histone acetyltransferase.

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Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3 '-phosphate-containing terminally gapped, linearized reporter plasmid.

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In the present study we use cell transfections, in vitro binding, co-immunoprecipitations, and reporter assays to show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300 and CREB binding protein associated factor and inhibits transcription by these coactivators.

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Additionally, ataxin-3 also binds coactivators like CBP, p300, and CBP and p300 associated factor (PCAF) and represses the respective coactivator mediated transcription.

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Similar to the polyQ-expansions of sizes> = 34 in the polysome associated protein ATXN2 causing Spinocerebellar Ataxia Type 2 (SCA2), polyQ expansions of sizes> = 52 in the deubiquitinating transcript[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, microarray gene expression profiling in MJD and SCA3 transgenic mice revealed that expanded ATX3 may cause cerebellar dysfunction and ataxia by disrupting the normal pattern of gene transcription.

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ATXN3 activates transcription, DNA-templated.

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ATXN3 activates transcription, DNA-templated. 2 / 2

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For example, ATXN3 has been shown to modulate transcription factor and repressor degradation by directly altering ubiquitin chains attached to such proteins [XREF_BIBR, XREF_BIBR].

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HTT affects ATXN3

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HTT decreases the amount of ATXN3.

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HTT decreases the amount of ATXN3. 3 / 3

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Similarly, Htt 100Q -N90 could also reduce the total Atx3 level.

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The results showed that, NLS-Atx7 93Q -N172 and Htt 100Q -N90 both caused reduction of the soluble Atx3 level, while MG132 treatment, to some extent, could reverse the decrease of Atx3 in the supernatant fraction.

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PQE Atx7 and Htt reduce the overall level of intracellular Atx3.

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HTT activates ATXN3.

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HTT activates ATXN3. 3 / 3

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In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes formutations causing HDL2, SCA17, SCA1, SCA2, SCA3, SCA8, SCA12 and DRPLA.

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However, blocking of the autophagic degradation exhibited no significant influence on the decline of Atx3 caused by Atx7 93Q -N172 or Htt 100Q -N90 (Supplemental Fig. 2B, D).

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The same group demonstrated the late-onset transgenic model with ataxin-3 driven by huntingtin promoter.

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HTT inhibits ATXN3.

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HTT inhibits ATXN3. 2 / 2

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PQE Atx7 and Htt reduce the soluble fraction of endogenous Atx3 but increase its insoluble aggregates.

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PQE Atx7 and Htt promote proteasomal degradation of intracellular Atx3.

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Ubiquitin activates ATXN3.

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Further studies indicate that ubiquitin-dependent activation of ataxin-3 at Lys-117 is important for its ability to reduce high molecular weight ubiquitinated species in cells.

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Cytoplasmic Ubiquitin Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.

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AT3 is composed of a structured globular N-terminal domain, the Josephin domain (JD), which displays ubiquitin hydrolase activity, followed by a disordered C-terminal tail containing two ubiquitin interacting motifs (UIMs) and the polyQ stretch of variable length, whose expansion beyond a certain threshold triggers SCA3 [XREF_BIBR, XREF_BIBR].

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Further studies indicate that ubiquitin dependent activation of ataxin-3 at Lys 117 is important for its ability to reduce high molecular weight ubiquitinated species in cells.

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For SCA 3, it is known that both normal and polyQ expanded ataxin-3 localize to mitochondria [XREF_BIBR] and that degradation of polyQ expanded ataxin-3 via the UPS is promoted by an ubiquitin ligase in the outer mitochondrial membrane called MITOL [XREF_BIBR].

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Ubiquitin inhibits ATXN3.

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Ataxin-3 limits ubiquitin chain length on CHIP substrates.

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SIRT1 affects ATXN3

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SIRT1 inhibits ATXN3.

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SIRT1 inhibits ATXN3. 3 / 3

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SIRT1 overexpression decreases MJD neuroinflammation.

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Furthermore, the pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice.

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The results show that SIRT1 overexpression significantly reduced the characteristic MJD neuropathology highlighting the role and importance of SIRT1 in the disease.

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SIRT1 inhibits mutated ATXN3. 2 / 2

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Finally, pulse-chase labeling reveals that ataxin-3 is degraded by the proteasome, with expanded ataxin-3 being as efficiently degraded as normal ataxin-3.

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Wild-type ATXN3 can be degraded by the proteasome, but whether other protein quality control pathways are involved in its turnover remains unknown.

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However, proteasome inhibition triggered polyQ expanded ATXN3 aggregation, a process that could be linked with the global proteostasis collapse induced by this treatment.

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In vitro studies revealed that inactive ataxin-3 was more slowly degraded by the proteasome and that this degradation occurred independent of ubiquitination.

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For ataxin-3 to be degraded by the proteasome, it needs to come into contact with this cellular machinery.

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The neuroprotective role of HSJ1 has been demonstrated in different disease models : it suppresses the aggregation of polyglutamine expanded proteins, significantly enhancing mutant huntingtin solubility in Huntington disease in cells and in mice, and promoting misfolded protein targeting to the ubiquitin-proteasome system; HSJ1a cooperates with Hsp70 to promote proteasome degradation of ataxin-3, a protein responsible for spinocerebellar ataxia type 3 (SCA3); HSJ1a prevented the aggregation of the misfolded C289G Parkin, a Parkinson disease associated ubiquitin protein ligase mutant, and restored its function in mitophagy.

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p45, an ATPase subunit of the 19S proteasome, interacts with ataxin-3 in vitro and stimulates the degradation of ataxin-3 in an in vitro reconstituted degradation assay system.

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Ataxin-3 is degraded by the proteasome.

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Proteasome activates ATXN3.

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Proteasome activates ATXN3. 1 / 1

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p45, an ATPase subunit of the 19S proteasome, targets the polyglutamine disease protein ataxin-3 to the proteasome.

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ATXN3 affects DNA Damage

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Mutated ATXN3 activates DNA Damage. 6 / 6

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Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

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Mutant ATXN3 induces genomic DNA damage in SCA3.

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Recent studies have shown elevated levels of DNA damage and strand breaks in peripheral blood lymphocytes in SCA3 patients [XREF_BIBR], indicating that mutant ATXN3 can induce DNA damage.

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Since mutant ATXN3 interacts with and inactivates PNKP, we next investigated whether ectopic expression of mutant ATXN3 induces DNA damage.

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ATXN3 activates DNA Damage. 3 / 3

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Enhanced accumulation of DNA damage has been observed in SCA3 patient post-mortem tissue and transgenic animal models of SCA3.

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Recently it was shown that the expression of polyQ expanded ataxin-3 can lead to genomic DNA damage in neuroblasts through inactivation of polynucleotide kinase 3 '-phosphatase (PNKP) XREF_BIBR.

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Additionally, a MJD and SCA3 in vitro model demonstrated that expanded ATX3 impairs the cell 's ability to respond to stress, alters antioxidant enzyme activities, and promotes mitochondrial DNA damage, which may lead to mitochondrial dysfunction.

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ATXN3 affects PTEN

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ATXN3 inhibits PTEN.

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In contrast, the two individual ATXN3 siRNAs (siATXN3_3 and _ 5) that caused the most profound PTEN induction (XREF_FIG and XREF_FIG) blunted Akt T308 phosphorylation in response to EGF (XREF_FIG).

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Alpha,alpha-trehalose affects ATXN3

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Alpha,alpha-trehalose activates ATXN3.

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Alpha,alpha-trehalose activates ATXN3. 4 / 4

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Trehalose mediated improvements in motor behaviour were associated with a reduction of the MJD associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells.

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XREF_FIG c a close to significant increase in the stride length (Control = 6.02 +/-0.12 cm, 2% trehalose = 6.51 +/-0.18 cm, p = 0.052, Student 's t test) and a significant decrease in the front base width (Control = 2.01 +/-0.08 cm, 2% trehalose = 1.77 +/-0.07 cm, p = 0.047; Student 's t test) was observed in MJD transgenic females treated with 2% trehalose, revealing that trehalose reduced the gait deficits of MJD transgenic females.

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Therefore, at 28weeks of treatment, a footprint analysis was additionally performed to investigate whether trehalose could rescue limb and gait ataxia of MJD transgenic mice.

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Alpha,alpha-trehalose inhibits ATXN3.

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However, we observed that trehalose significantly decreased the diameter of mutant ataxin-3 aggregates in a representative lobule (lobule IX) of the cerebellum (Control = 1.91 +/-0.03 microm; 2% trehalose = 1.80 +/-0.03 microm; p = 0.0197; Fig.

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Trehalose reduces cerebellar atrophy and mutant ataxin-3 aggregate size in Purkinje cells of Machado-Joseph disease transgenic mice.

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Alpha,alpha-trehalose inhibits ATXN3. 1 / 1

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Alpha,alpha-trehalose decreases the amount of ATXN3.

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Alpha,alpha-trehalose decreases the amount of mutated ATXN3. 2 / 2

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Trehalose activates autophagy and reduces mutant ataxin-3 protein levels in neuro-2a cells expressing mutant ataxin-3.

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Altogether, these data shows that trehalose activates autophagy and reduces mutant ataxin-3 levels in this in vitro model of MJD.

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ATXN3 affects MDC1

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ATXN3 activates MDC1.

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ATXN3 activates MDC1. 4 / 7

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Loss of ataxin-3 markedly decreases the chromatin dwell time of MDC1 at DSBs, which can be fully reversed by co-depletion of RNF4.

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Thus, while RNF4 reduces the chromatin retention of MDC1 in wild-type cells (Galanty etal, 2012), ataxin-3 has the opposite effect and increases the retention time of MDC1 on chromatin.

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We also show that ataxin-3 promotes efficient MDC1 dependent DSB repair by NHEJ and HR.

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As a result, Ataxin-3 promotes prolonged retention of MDC1, resulting in reduced recruitment of 53BP1 and BRCA1.

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ATXN3 increases the amount of MDC1.

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ATXN3 increases the amount of MDC1. 1 / 1

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Our study revealed that depletion of ataxin-3 increases the levels of ubiquitylated MDC1, while at the same time reducing its residence time at DNA breaks, consistent with the idea that ubiquitylation of MDC1 is the primary signal that regulates its release from chromatin.

28275011

FBXL3 affects ATXN3

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FBXL3 inhibits ATXN3.

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FBXL3 inhibits ATXN3. 5 / 5

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To evaluate if FBXL3 mediated reduction of ATXN3 abundance occurs via the SCF and CUL1 ubiquitination complex, we co-electroporated plasmid overexpressing FBXL3 while also decreasing CUL1 with siRNAs against CUL1 (XREF_FIG).

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While the specific mechanism by which FBXL3 mediates reduction of ATXN3 abundance remains to be defined, the development of small molecules that activate this mechanism could be of therapeutic value for SCA3.

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If FBXL3 knockdown increases ATXN3 abundance, then its overexpression would be expected to decrease ATXN3 protein levels.

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Knockdown of CUL1 abolished FBXL3 mediated reduction of normal ATXN3, but only accounted for about half of the observed FBXL3 facilitated decrease of pathogenic ATXN3 (XREF_FIG), suggesting that FBXL3 handles or recognizes normal and mutant ATXN3 differently.

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It implies that polyQ expanded Atx3 impairs the function of P97 complex that is capable of down-regulating the neddylation level in cells.

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These results demonstrate that polyQ expanded Atx3 sequesters P97 molecules into insoluble aggregates or inclusions, which is dependent on the specific interaction via the VBM motif of Atx3.

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PolyQ expanded Atx3 sequesters P97 to aggregates through specific interaction.

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However, in the pellet fractions, Atx3 100Q sequestered more P97 molecules into aggregates than Atx3 22Q, due to an increasing amount of Atx3 100Q in the pellet (XREF_FIG).

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Because polyQ expanded Atx3 can sequester endogenous P97 into insoluble aggregates, we resorted to the previously established experiment to explore whether aggregation of Atx3 interferes with the function of P97.

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However, aggregation of Atx3 100Q could sequester more endogenous P97 than that of Atx3 22Q (XREF_FIG).

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We have found that aggregation of polyQ expanded Atx3 can sequester P97 and Ub conjugates into the protein aggregates or inclusions through specific interactions both in vitro and in cells.

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SUMO1 affects ATXN3

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SUMO1 activates ATXN3.

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SUMO1 activates ATXN3. 4 / 5

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Interestingly, SUMO-1 overexpression enhanced the co-localization of ataxin-3 and autophagy marker LC3 without increasing LC3 puncta formation suggesting that SUMO-1 is involved in the substrate recruitment rather than the induction of autophagy.

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In addition, we further confirmed SUMO-1 modification decreased the degradation and enhanced the stability of mutant-type ataxin-3 by chase assay.

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By contrast, SUMO-1 coexpression significantly enhanced the colocalization of LC3 and ataxin-3 signals (highlighted by arrows) (XREF_FIG, upper panels).

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In addition to the SUMO dependent recruitment of ATXN3, free SUMO1 can also stimulate ATXN3 DUB activity against Ub-K63 chain in vitro.

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SUMO1 inhibits ATXN3.

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SUMO1 inhibits ATXN3. 2 / 2

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These results together indicate that SUMO-1 promotes the degradation of ataxin-3 via autophagy and the putative SIM of ataxin-3 plays a role in this process.

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In conclusion, we present evidence that SUMO-1 induces ataxin-3 degradation via autophagy although UPS also contribute to this process to a certain extent.

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Caspase affects ATXN3

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Caspase activates ATXN3.

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Caspase activates ATXN3. 5 / 5

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CDK5 protects from caspase induced Ataxin-3 cleavage and neurodegeneration.

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In line with previous research, there was no increased caspase mediated cleavage of expanded ataxin-3 compared to non expanded ataxin-3.

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Finally, caspase mediated cleavage of expanded ataxin-3 resulted in increased ataxin-3 aggregation, suggesting a potential role for caspase mediated proteolysis in spinocerebellar ataxia type-3 pathogenesis.

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Whether caspase mediated ataxin-3 cleavage is indeed a major contributor to SCA3 pathogenesis remains to be determined through future in vivo experiments.

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A recent publication reported involvement of CDK5 in caspase mediated ataxin-3 cleavage, showing that RNAi of CDK5 in a Drosophila model for SCA 3 resulted in an enhanced SCA 3 toxicity [XREF_BIBR].

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Caspase inhibits ATXN3.

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Caspase inhibits ATXN3. 2 / 2

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We next asked whether reduction in caspase cleavage modulates Ataxin-3 protein toxicity.

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In a Drosophila model of SCA3, mutation of proposed caspase cleavage sites in ATXN3 dramatically reduces production of polyQ enriched fragments [XREF_BIBR] and ameliorates degeneration caused by polyQ expanded ATXN3.

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ATXN3 affects Cell Survival

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ATXN3 inhibits Cell Survival.

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ATXN3 inhibits Cell Survival. 2 / 5

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ATXN3 activates DNA repair. 3 / 3

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Clearly, loss of ATXN3 can impair multiple DNA repair processes.

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As a DUB, ATXN3 stabilizes the ATR downstream targets Chk1 (Checkpoint Kinase 1) and p53 (tumor protein 53), both of which function to delay cell cycle progression and promote DNA repair.

31669734

ATXN3 affects SOD2

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ATXN3 increases the amount of SOD2.

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ATXN3 increases the amount of SOD2. 2 / 4

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Finally and consistent with a regulatory role of ATXN3 in SOD2 expression, knockdown of endogenous ATXN3 by RNA interference represses the expression of SOD2.

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ATXN3 interacts with and stabilizes the forkhead box O (FOXO) transcription factor FOXO4, and upon oxidative stress they both translocate to the nucleus and activate manganese superoxide dismutase (SOD2) transcription which in turn protects cells from oxidative damage.

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ATXN3 bound to FOXO4 increases the amount of SOD2. 1 / 1

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It is notable that Atxn3 interacts with mammalian FOXO4 and activates basal and stress induced expression of SOD2; this is opposite in C. elegans where Atxn3 KO exhibits enhanced transcription of sod-3 through DAF-16.

reach

It was discovered that inhibition of Ca 2+ -dependent protease calpain suppressed aggregation of polyglutamine expanded Atxn3 in transfected cells [XREF_BIBR].

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The authors hypothesized that calcium dependent activation of proteases causes the cleavage of ATXN3 leading to protein aggregation as a result.

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It was discovered that inhibition of Ca 2+ -dependent protease calpain suppressed aggregation of polyglutamine expanded Atxn3 in transfected cells.

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Most of these findings parallel our previous studies of Ca 2+ signaling in HD and SCA3 mouse models and indicate that deranged Ca 2+ signaling contributes to pathogenesis of at least these three polyglutamine-expansion disorders.

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Administration of an activator of calcium activated potassium channels, SKA-31, partially corrects abnormal Purkinje cell firing and improves motor function in SCA3 mice.

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ATXN3 affects RNF4

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ATXN3 inhibits RNF4. 1 / 6

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In particular, we suggest that ataxin-3 is a functional antagonist of RNF4 during the signaling and repair of DSBs where it acts as a SUMO activated DUB on at least one of the identified RNF4 substrates : MDC1.

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Smo-1 affects ATXN3

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Smo-1 inhibits ATXN3.

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Smo-1 inhibits ATXN3. 5 / 5

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These findings, together with the effects of the autophagy inhibitor 3-MA, led us to speculate as to whether autophagy-lysosome system plays more important role in SUMO induced ataxin-3 degradation.

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In the future studies, different substitutions should be designed and tested to confirm the requirement of SIM for SUMO induced degradation of ataxin-3.

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Proteolytic pathways mediating SUMO induced ataxin-3 degradation.

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On the other hand, the observation that MG132 blocked SUMO induced degradation of ataxin-3, although the effect was not strong, suggested a role of UPS for this process.

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Interestingly, the autophagy inhibitor 3-MA reduced SUMO induced degradation of ataxin-3 much more effectively.

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Smo-1 activates ATXN3.

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Smo-1 activates ATXN3. 1 / 1

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On the other hand, our findings that SUMO overexpression did not increase LC3 puncta formation and instead enhanced the co-localization of ataxin-3 with LC3 raise a possibility that SUMO-1 overexpression increases SUMOylation of certain components involved in substrate (cargo) recruitment for autophagy, which in turn accelerates the turnover of substrates.

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DNAJB1 affects ATXN3

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DNAJB1 inhibits ATXN3. 4 / 5

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Over-expression of the Drosophila DNAJB1 homolog, dHDJ1, suppressed polyQ Htt- and ATXN3 dependent toxicity [XREF_BIBR, XREF_BIBR], and the effect of dHDJ1 on ATXN3 mediated toxicity was enhanced by over-expression with wildtype Hsp70 but inhibited by co-expression with a dominant negative mutant of Hsp70.

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An overexpression of HSP40 and HDJ -2 suppressed ataxin-3 and ataxin-1 aggregation in vitro [XREF_BIBR, XREF_BIBR], but not in huntingtin exon 1 overexpressing cell lines [XREF_BIBR].

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DNAJB1 was identified to suppress aggregate formation of ATXN3, but aggregation of the S256A mutant of ATXN3 could not be prevented by DNAJB1, it is still unclear whether DNAJB1 has preferential affinity for phosphorylated ATXN3.

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For example, HSP40 and HSP70 were reported to localize in the intranuclear aggregates formed by mutant ataxin-3 and that overexpression of HSP40 reduces aggregation of truncated and full-length Atx3 XREF_BIBR.

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DNAJB1 inhibits mutated ATXN3. 1 / 1

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In transfected cells, overexpression of either of two Hsp40 chaperones, the DNAJ protein homologs HDJ-1 and HDJ-2, suppresses aggregation of truncated or full length mutant ataxin-3.

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ATXN3 affects cell population proliferation

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ATXN3 activates cell population proliferation.

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ATXN3 activates cell population proliferation. 4 / 4

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Functionally, Ataxin-3 overexpression promoted cell proliferation, and Ataxin-3 knockdown inhibited cell proliferation.

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Ataxin-3 promotes testicular cancer cell proliferation by inhibiting anti-oncogene PTEN.

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Moreover, various gain/loss functional assays were performed to indicate that ATXN3 overexpression enhanced ATC cell proliferation and metastasis.

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34428509

ATXN3 inhibits cell population proliferation.

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ATXN3 inhibits cell population proliferation. 1 / 1

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We found that transfection of miR-619-5p or si-ATXN3 alone reduced cell proliferation ability, and the combined transfection enhanced this effect.

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ATXN3 affects VCP

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ATXN3 activates VCP. 4 / 4

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We present evidence that atx3 may promote p97 associated deubiquitination to facilitate the transfer of polypeptides from p97 to the proteasome.

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Atx3 promotes p97 associated deubiquitination.

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Various ataxin-3 protein domains contribute to its toxicity, including the valosin-containing protein (VCP)-binding motif (VBM).

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In contrast, evidence has also shown that ataxin-3 may promote p97 associated deubiquitination to facilitate the transfer of ERAD substrates to the proteasome XREF_BIBR.

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ATXN3-C14A activates VCP. 1 / 1

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We first tested whether the expression of atx3 C14A inhibits the p97 dependent degradation of misfolded TCRalpha, a type I transmembrane protein targeted for retrotranslocation due to the lack of its assembly partners.

17000876

AMFR affects ATXN3

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Ataxin-3 is, for instance, able to repress matrix metalloproteinase-2 (MMP-2) transcription, and improved nuclear localisation of ataxin-3 through phosphorylation enhances this transcriptional repression [XREF_BIBR].

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ATXN3 bound to HDAC3 decreases the amount of MMP2. 1 / 1

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Here we show that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3.

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Resveratrol activates ATXN3.

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Resveratrol activates mutated ATXN3. 1 / 1

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Resveratrol activates ATXN3. 1 / 1

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No evidence text available

17885668

N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal affects ATXN3

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates ATXN3.

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N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal activates ATXN3. 2 / 2

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Azure C or MG132 that inhibit HSP70 function or proteasome activity can also significantly increase the protein level of Atx3 71Q (XREF_FIG), as in the case of Atx3 22Q (XREF_FIG & XREF_FIG).

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On the other hand, the observation that MG132 blocked SUMO induced degradation of ataxin-3, although the effect was not strong, suggested a role of UPS for this process.

| 5

CAST increases the amount of ATXN3.

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CAST increases the amount of ATXN3. 2 / 2

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Calpeptin (a calpain inhibitor) decreased levels of atxn3 cleaved fragments in atxn3-84Q zebrafish and rescued the motor phenotype, but it also removed all ATXN3 expanded protein due to an increase in autophagic flux (indicated by reduced p62 levels and increased LC3II levels) that cleared autolysosomes.

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CAST activates ATXN3.

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CAST activates mutated ATXN3. 1 / 1

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Calpastatin, a calpain inhibitor, decreases the nuclear uptake and aggregation of mutant ATXN3, delaying neurodegeneration in SCA3 mouse models.

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CAST activates ATXN3. 1 / 1

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CAST inhibits ATXN3.

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CAST inhibits mutated ATXN3. 1 / 1

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Calpastatin, a calpain inhibitor, decreases the nuclear uptake and aggregation of mutant ATXN3, delaying neurodegeneration in SCA3 mouse models.

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Sirolimus affects ATXN3

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Sirolimus decreases the amount of ATXN3. 4 / 4

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Administration of a rapamycin analogue, CCI-779, to a SCA3 mouse model with an expanded ataxin-3 containing 70 glutamines, reduced soluble levels of expanded ataxin-3, decreased the number of aggregates in brains, and ameloriated motor dysfunction.

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Consistent with the Drosophila data, the rapamycin analogue CCI-779 reduces both mutant huntingtin and ataxin-3 levels and ameliorates toxicity in mouse models of HD and spinocerebellar ataxia type 3, respectively XREF_BIBR, XREF_BIBR.

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Consistent with the Drosophila data, the rapamycin analogue CCI-779 reduces both mutant huntingtin and ataxin-3 levels, thereby attenuating toxicity in mouse models of HD and spinocerebellar ataxia type 3, respectively.

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CCI-779, a rapamycin ester (i.e., an analogue of rapamycin) reduces both mutant huntingtin and ataxin-3 levels, thereby attenuating toxicity in mouse models of HD and SCA3, respectively XREF_BIBR.

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Hsa-miR-6851-5p affects ATXN3

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Hsa-miR-6851-5p decreases the amount of ATXN3. 4 / 4

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No evidence text available

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No evidence text available

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No evidence text available

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Hsa-miR-6799-5p affects ATXN3

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Hsa-miR-6799-5p decreases the amount of ATXN3. 4 / 4

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No evidence text available

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No evidence text available

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biopax:mirtarbase

No evidence text available

23446348

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No evidence text available

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Hsa-miR-3689d affects ATXN3

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Hsa-miR-3689d decreases the amount of ATXN3. 4 / 4

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No evidence text available

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No evidence text available

19536157

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biopax:mirtarbase

No evidence text available

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biopax:mirtarbase

No evidence text available

23446348

ATXN3 affects localization

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ATXN3 activates localization. 4 / 4

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The product of this gene, ataxin-3, associates to and is phosphorylated by CK2 175 (Fig. 3d ), which induces its nuclear localization and stabilization, and enhances the formation of inclusions.

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d Spinocerebellar ataxia type 3 (SCA3): CK2 associates to and phosphorylates ataxin-3, thus promoting its nuclear localization and stabilization, and enhancing the formation of inclusions.

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Coiled-Coil Structures of SCA3 polyQ Proteins Promote Their Nuclear Localization.

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Mapping studies showed that two regions of Atx3, the Josephin domain and the C-terminus, regulated heat shock induced nuclear localization.

19843543

Temsirolimus affects ATXN3

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Temsirolimus inhibits ATXN3.

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Temsirolimus inhibits ATXN3. 3 / 3

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A drug that increases autophagy, temsirolimus, decreased ataxin-3 both in soluble and aggregate forms and reduced pathology in a SCA3-transgenic line.

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This analysis identified only 16 genes (XREF_TABLE) whose expression was decreased in transgenic ataxin-3 mice and increased in transgenic mice treated with temsirolimus.

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Of the first three genes we looked at, we confirmed a decrease in expression of Usp15 and Grik2 between wild-type and ataxin-3 transgenic mice, which were reversed in mice treated with temsirolimus (XREF_FIG B).

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Temsirolimus activates ATXN3.

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Temsirolimus activates ATXN3. 1 / 1

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However, consistent with mTOR inhibition inducing autophagy, ataxin-3 transgenic mice treated with temsirolimus showed decreased levels of phosphorylated S6 ribosomal protein (a downstream target of the mTOR pathway), and levels the mutant protein in the cytosol were decreased, as were the number of aggregates.

20007218

HSPA affects ATXN3

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HSPA activates ATXN3.

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HSPA activates ATXN3. 3 / 3

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It was previously reported that overexpression of CHIP increases the ubiquitination and degradation rates of polyQ expanded Atx3, which is also enhanced by HSP70 XREF_BIBR.

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Another example of the gene-to-drug transition is the rescue of Atx3 and alpha-Syn toxicity by Hsp70.

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The increased turnover of both ataxin-3 variants induced by Hsp70 and the large number of Hsp70 family chaperones in the MS analysis suggests that a subpopulation of ataxin-3 adopts a non native confo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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HSPA inhibits ATXN3.

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HSPA inhibits mutated ATXN3. 1 / 1

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Li et al. (2018) discussed whether the upregulation of the neurotrophin IGF-1 and the HSP70 chaperone molecular pathway could suppress the mutant ataxin-3 protein toxicity in MSC-treated SCA3 mice [38].

| PMC

HSP104 affects ATXN3

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HSP104 inhibits ATXN3.

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HSP104 inhibits ATXN3. 3 / 3

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Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities.

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Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ induced degeneration, whereas Hsp70 was ineffective.

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XREF_BIBR Notably, Hsp104 suppressed toxicity of a C-terminal ataxin-3 fragment when expressed even after the onset of polyglutamine induced degeneration.

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HSP104 activates ATXN3.

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HSP104 activates ATXN3. 1 / 1

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Hsp104 mitigates toxicity of truncated MJD, but enhances toxicity of the full-length MJD.

24039611

ATXN3 affects Proteasome

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ATXN3 activates Proteasome.

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ATXN3 activates Proteasome. 1 / 3

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Whether CHIP is the primary mediator of ubiquitin dependent degradation of ataxin-3 is controversial : XREF_BIBR reported that CHIP ubiquitinates ataxin-3 and directs it to the proteasome for degradation, whereas XREF_BIBR reported that another ubiquitin ligase, E4B, mediates ataxin-3 degradation while CHIP has no effect.

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ATXN3 inhibits Proteasome.

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ATXN3 inhibits Proteasome. 1 / 1

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Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment

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ATXN3 affects EFNA3

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ATXN3 decreases the amount of EFNA3. 3 / 3

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Both normal and expanded ATXN3 significantly repressed Efna3 transcription by approximately 20% but had no effect on expression of the control pGL3 luciferase vector (XREF_FIG).

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To identify which histone acetylases and regulators are likely involved in establishing the histone acetylation and enhanced gene expression of Efna3 induced by the loss of ATXN3, we measured their nuclear protein levels in both Atxn3-KO and WT cells.

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These results indicate that ATXN3 represses Efna3 transcription by acting, either directly or indirectly, on the promoter region.

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Modified ATXN3 decreases the amount of EFNA3. 1 / 1

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Overexpression of normal or expanded ATXN3 was sufficient to repress Efna3 expression, supporting a role for ATXN3 in regulating Ephrin signaling.

30231063

ATXN3 affects BAX

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ATXN3 increases the amount of BAX.

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ATXN3 increases the amount of BAX. 2 / 3

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BECN1 activates mutated ATXN3. 2 / 2

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Additional evidence supporting autophagy induction as a viable therapeutic target is the fact that lentiviral mediated overexpression of the autophagy protein beclin-1 increases clearance of mutant ATXN3 and decreases aggregates in a MJD rat model.

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As a corollary, overexpression of beclin 1 can stimulate the autophagic flux and promote clearance of the mutant ataxin-3 in brains of SCA3 mouse models.

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BECN1 activates ATXN3. 1 / 1

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ATXN3 inhibits endoplasmic reticulum.

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Furthermore, we demonstrated that ATXN3 promoted breast cancer cell metastasis via KLF4 in vitro and in vivo.

31563563

ATXN3 affects LY6E

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ATXN3 activates LY6E. 3 / 3

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24780882

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SCA2 and SCA3 are caused by polyglutamine expansions in ataxin2 and ataxin3, respectively [XREF_BIBR, XREF_BIBR].

20383523

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Ataxin gene variants in ATXN1, ATXN2, ATXN3, and ATXN7 cause SCA1, SCA2, SCA3, and SCA7, respectively.

29168350

ATXN3 affects Caspase

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ATXN3 activates Caspase. 3 / 3

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While it is reasonable to hypothesize that expanded Ataxin-3 protein may activate caspases that proteolyze Ataxin-3, the observation that normal Ataxin-3, which does not cause neurodegeneration, is also cleaved, suggests that cleavage is not necessarily a consequence of apoptosis.

19783548

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The data with zVAD-fmk indicated that Ataxin-3 is a target of caspases also in Drosophila cells.

19783548

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19783548

Endoplasmic reticulum affects ATXN3

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Endoplasmic reticulum inhibits ATXN3.

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Endoplasmic reticulum inhibits ATXN3. 2 / 2

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Moreover, ataxin-3 also induces a reduction in CHIP levels.

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ATXN3 activates STUB1.

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ATXN3 affects EIF5A2

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ATXN3 activates EIF5A2.

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ATXN3 activates EIF5A2. 2 / 2

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The deubiquitinating enzyme ATXN3 promotes the progression of anaplastic thyroid carcinoma by stabilizing EIF5A2.

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Mechanistically , ATXN3 promotes EIF5A2 expression by directly binding to EIF5A2 to reduce its ubiquitination and degradation .

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ATXN3 increases the amount of EIF5A2.

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ATXN3 increases the amount of EIF5A2. 1 / 1

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Mechanistically, ATXN3 promotes EIF5A2 expression by directly binding to EIF5A2 to reduce its ubiquitination and degradation.

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ATXN3 affects CASP3

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ATXN3 activates CASP3. 2 / 2

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Ataxin gene variants in ATXN1, ATXN2, ATXN3, and ATXN7 cause SCA1, SCA2, SCA3, and SCA7, respectively.

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Mutated ATXN3 activates CASP3. 1 / 1

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We next assessed whether blocking PKCdelta phosphorylation by inhibiting c-Abl kinase activity ameliorates mutant ATXN3 mediated caspase-3 activation.

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Temsirolimus affects ATXN3

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Temsirolimus decreases the amount of ATXN3.

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Temsirolimus decreases the amount of ATXN3. 1 / 1

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Temsirolimus reduces cytoplasmic levels of expanded ataxin-3.

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Temsirolimus decreases the amount of ATXN3. 1 / 1

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It also removed cellular aggregates of mutant Htt and improved motor performance in a mouse model of HD, reduced α-synuclein aggregation and afforded neuroprotection in a lesion-based model of PD and depleted mutant ataxin 3 in a mouse model of supraspinal cerebellar ataxia type 3 (REFS133,138,139) .

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Temsirolimus increases the amount of ATXN3.

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Temsirolimus increases the amount of mutated ATXN3. 1 / 1

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Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected.

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Res affects ATXN3

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Res inhibits ATXN3.

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28912527

Res decreases the amount of ATXN3.

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Res decreases the amount of mutated ATXN3. 1 / 1

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Our data suggest that CA and Res may through upregulation of the autophagy process decrease the expression of mutant ataxin-3 and protein aggregates, resulting in restoration of the Hsp27 and Bcl-2 protein expression in tBH treated SK-N-SH-MJD78 cells.

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Res activates ATXN3.

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Res activates mutated ATXN3. 1 / 1

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28912527

ATXN3 affects ITGA5

In conclusion, our findings do not provide strong evidence that ataxin-3, a DUB implicated in protein quality control, modulates polyglutamine induced disease in a knock-in mouse model of HD.

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ATXN3 affects GST

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We found that the anti-aggregation effect of ROCK inhibitors was not limited to the mutant htt and AR and that Y-27632 was also able to reduce the aggregation of ataxin-3 and atrophin-1 with expanded polyQ.

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Pirinixic acid decreases the amount of ATXN3. 1 / 1

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No evidence text available

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Pirinixic acid activates ATXN3.

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Pirinixic acid activates ATXN3. 1 / 1

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Chloroquine inhibits mutated ATXN3. 1 / 1

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In addition, SIRT1 overexpression induced a decrease of mutant ataxin-3, which was prevented by chloroquine (XREF_FIG).

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Chloroquine activates ATXN3.

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Chloroquine activates ATXN3. 1 / 1

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Ube4b leads to the deubiquitination of ATXN3. 1 / 1

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UFD2a markedly promoted ubiquitylation and degradation of MJD1 with expanded polyglutamine tract, resulting in the clearance of MJD1 protein.

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Ube4b activates ATXN3.

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Ube4b activates ATXN3. 1 / 1

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SDS inhibits ATXN3. 1 / 1

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The presence of 1 mM SDS eliminated the lag phase of all the ataxin-3 variants, resulting in an immediate exponential growth phase with a rate independent of polyQ length.

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SDS activates ATXN3.

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SDS activates ATXN3. 1 / 1

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SDS Modulates SDS-soluble Aggregation of Ataxin-3.

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Rad23 affects ATXN3

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Rad23 increases the amount of ATXN3.

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Rad23 increases the amount of ATXN3. 1 / 1

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In this study, we examined the effect of individual Culs on SCA3 pathogenesis, and found that the knockdown of Cul1 expression enhances SCA3 induced neurodegeneration and reduces the solubility of expanded SCA3-polyQ proteins.

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CUL1 activates ATXN3.

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CUL1 activates ATXN3. 1 / 1

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ATXN3 inhibits transport. 1 / 1

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Aggregated disease protein may physically block transport; expression of a mutant ataxin-3 fragment in Drosophila, for example, was found to cause axonal blockages.

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ATXN3 activates transport.

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ATXN3 activates transport. 1 / 1

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Recent evidence indicates that aggresome formation is mediated by dynein and dynactin mediated microtubule based transport of misfolded proteins to the centrosome and involves several regulators, including histone deacetylase 6, E3 ubiquitin protein ligase parkin, deubiquitinating enzyme ataxin-3, and ubiquilin-1.

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ATXN3 affects superoxide

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ATXN3 increases the amount of superoxide.

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ATXN3 increases the amount of superoxide. 1 / 1

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ATXN3 activates superoxide.

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ATXN3 activates superoxide. 1 / 1

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ATXN3 inhibits metabolic process. 1 / 1

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ATXN3 activates metabolic process.

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ATXN3 activates metabolic process. 1 / 1

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Ataxin-3 Links NOD2 and TLR2 Mediated Innate Immune Sensing and Metabolism in Myeloid Cells.

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ATXN3 affects manganese atom

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ATXN3 increases the amount of manganese atom.

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ATXN3 activates manganese atom.

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ATXN3 activates manganese atom. 1 / 1

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The wild-type ATXN3 protein stimulated, and in contrast, the mutant ATXN3 dramatically diminished, the 3 ' phosphatase activity of PNKP in vitro (Chatterjee et al; Figs.

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ATXN3 inhibits Phosphatase. 1 / 1

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ATXN3 inhibits Glu-Ser. 1 / 1

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Structure of the Targeted Atxn3 Gene and the Expression of Ataxin-3 in Targeted ES Cells.

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ATXN3 activates Glu-Ser.

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ATXN3 activates Glu-Ser. 1 / 1

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Mutated ATXN3 activates CHEK2. 1 / 1

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TF affects ATXN3

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TF activates ATXN3. 1 / 1

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We selected Foxo and Cut as the most likely TF targets of SCA3 polyQ proteins because they showed the strongest effects on dendrite branch points upon their knockdown or overexpression (XREF_TABLE).

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TBP affects ATXN3

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MYB affects ATXN3

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MYB decreases the amount of ATXN3. 1 / 1

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No evidence text available

MTERF5 affects ATXN3

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MTERF5 inhibits ATXN3. 1 / 1

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Loss of MDA1 function caused up-regulation of the RpoTp and SCA3 nuclear gene encoding a plastid RNA polymerase and modified the steady-state levels of chloroplast gene transcripts.

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MBNL1 affects ATXN3

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MBNL1 activates ATXN3. 1 / 1

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MBL2 affects ATXN3

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MBL2 activates ATXN3. 1 / 1

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However, over-expression of mbl enhanced SCA3 mediated neurodegeneration in the SCA3 D. melanogaster model.

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MAX affects ATXN3

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ATXN3 affects double-strand break repair

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Mutated ATXN3 inhibits DNA polymerase. 1 / 1

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These data further support the idea that the mutant ATXN3 specifically blocks the activity of PNKP, but not that of DNA polymerase or ligase (XREF_SUPPLEMENTARY).

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