ATXN3

Summary

ATXN3 (ataxin 3, HGNC:7106) is a protein-coding gene on chromosome 14q32.12, encoding Ataxin-3 (P54252). Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates.

Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 4287 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Machado-Joseph disease (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 110 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes
• MANE Select transcript: NM_004993

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7106
Approved symbol	ATXN3
Name	ataxin 3
Location	14q32.12
Locus type	gene with protein product
Status	Approved
Aliases	ATX3, JOS
Ensembl gene	ENSG00000066427
Ensembl biotype	protein_coding
OMIM	607047
Entrez	4287

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 19 nonsense_mediated_decay, 17 protein_coding, 16 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000340660, ENST00000359366, ENST00000393287, ENST00000429774, ENST00000454964, ENST00000502250, ENST00000503767, ENST00000504047, ENST00000506466, ENST00000507965, ENST00000511362, ENST00000515746, ENST00000526872, ENST00000532032, ENST00000545170, ENST00000553287, ENST00000553309, ENST00000553488, ENST00000553491, ENST00000553498, ENST00000553570, ENST00000553686, ENST00000554040, ENST00000554214, ENST00000554350, ENST00000554491, ENST00000554592, ENST00000554672, ENST00000554673, ENST00000554994, ENST00000555381, ENST00000555816, ENST00000555958, ENST00000556082, ENST00000556220, ENST00000556274, ENST00000556288, ENST00000556315, ENST00000556339, ENST00000556374, ENST00000556644, ENST00000556671, ENST00000556898, ENST00000556958, ENST00000557030, ENST00000557311, ENST00000564606, ENST00000568290, ENST00000642417, ENST00000642896, ENST00000644486, ENST00000644720, ENST00000646485, ENST00000647161, ENST00000860909

RefSeq mRNA: 10 — MANE Select: NM_004993 NM_001127696, NM_001127697, NM_001164776, NM_001164778, NM_001164779, NM_001164780, NM_001164781, NM_001424070, NM_004993, NM_030660

CCDS: CCDS32143, CCDS45154, CCDS53908, CCDS73680, CCDS9900

Canonical transcript exons

ENST00000644486 — 11 exons

Exon	Start	End
ENSE00001383144	92058552	92064414
ENSE00002033783	92106529	92106582
ENSE00003477115	92093252	92093318
ENSE00003499200	92093746	92093831
ENSE00003530935	92083126	92083258
ENSE00003574977	92088730	92088817
ENSE00003646843	92096674	92096838
ENSE00003649810	92096093	92096137
ENSE00003654296	92080965	92081061
ENSE00003688920	92082300	92082466
ENSE00003788002	92070935	92071053

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 96.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1976 / max 221.5980, expressed in 1705 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144577	9.0438	1699
207337	0.1537	40

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.73	gold quality
colonic epithelium	UBERON:0000397	95.24	gold quality
tendon	UBERON:0000043	94.38	gold quality
tendon of biceps brachii	UBERON:0008188	93.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.65	gold quality
endothelial cell	CL:0000115	91.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.81	gold quality
sural nerve	UBERON:0015488	89.84	gold quality
monocyte	CL:0000576	89.59	gold quality
mononuclear cell	CL:0000842	88.83	gold quality
leukocyte	CL:0000738	88.53	gold quality
pericardium	UBERON:0002407	88.12	gold quality
right uterine tube	UBERON:0001302	88.02	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.86	gold quality
tibial nerve	UBERON:0001323	87.79	gold quality
saphenous vein	UBERON:0007318	87.34	gold quality
skin of abdomen	UBERON:0001416	87.32	gold quality
skin of leg	UBERON:0001511	87.30	gold quality
corpus callosum	UBERON:0002336	87.22	gold quality
upper leg skin	UBERON:0004262	87.00	gold quality
trigeminal ganglion	UBERON:0001675	86.88	gold quality
nipple	UBERON:0002030	86.73	gold quality
skin of hip	UBERON:0001554	86.68	gold quality
zone of skin	UBERON:0000014	86.55	gold quality
body of uterus	UBERON:0009853	86.55	gold quality
left ovary	UBERON:0002119	86.49	gold quality
tonsil	UBERON:0002372	86.46	gold quality
endometrium	UBERON:0001295	86.44	gold quality
pylorus	UBERON:0001166	86.38	gold quality
peritoneum	UBERON:0002358	86.34	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO4, TP53

miRNA regulators (miRDB)

219 targeting ATXN3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960

Literature-anchored findings (GeneRIF, showing 40)

• Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. (PMID:12084819)
• examination of structural instability and fibrillar aggregation of non-expanded form under high pressure and temperature (PMID:12766160)
• expression of mutant form is involved in down regulation of heat shock protein 27 in neuronal and non-neuronal cells (PMID:12832059)
• functional ubiquitin-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates (PMID:12857950)
• Spinocerebellar ataxia type 3 presenting as an L-DOPA responsive dystonia phenotype in a Chinese family.and SCA 3 should be considered a differential diagnosis in adult patients who present with DRD phenotype and with a positive family history. (PMID:12873751)
• ataxin-3 human and mouse protein sequences share a highly conserved N-terminus and differ only in the length of the glutamine repeats and in the C-terminus; the domain architecture of both is detailed (PMID:12914917)
• The significance of SCA3 mutation in either sporadic or familial young-onset dopa-responsive parkinsonism suggestive of Parkinson’s disease is not proven in a population of 85 Serbian patients. (PMID:12940846)
• ataxin-3 interacts with ubiquitinated proteins, can bind the proteasome, and, when the gene harbors an expanded repeat length, can interfere with the degradation of a well-characterized substrate. Additionally, ataxin-3 associates with Rad23 and VCP/p97 (PMID:12944474)
• Ataxin-3 binds polyubiquitylated proteins and has deubiquitylating activity. (PMID:14559776)
• ataxin-3 is a poly-ubiquitin-binding protein (PMID:14602712)
• ataxin-3 folds reversibly via a single intermediate; partial destabilization of ataxin-3 by chemical denaturation leads to the formation of fibrillar aggregates by the non-pathological variant (PMID:14659761)
• A soluble human ataxin-3 variant with a moderately expanded polyQ tract of 36 glutamine residues gives rise to amyloid fibrils on increasing temperature above 40 degrees C. (PMID:14661975)
• metabolic changes associated with transgenic mouse model of spinocerebellar ataxia 3 (PMID:14679302)
• These results strongly suggest that ADCA families can be traced back to common ancestors in particular parts of the Netherlands. (PMID:15026782)
• Transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter exhibit narcolepsy-cataplexy and postnatal loss of orexin-positive neurons (PMID:15128861)
• 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 (PMID:15140190)
• The molecular architecture of CAG repeats in mutant SCA3 transcripts was studied. (PMID:15223312)
• Data report sequence-independent discrimination of mutant and wild-type ataxin-3 alleles by small interfering RNA. (PMID:15236410)
• exploration of protein architectures of ataxin-2 and ataxin-3 (PMID:15265035)
• The results of this study indicate that the clinical entity of Machado-Joseph disease can occur with 51 trinucleotide repeats, and that the clinical features of Machado-Joseph disease might cover a wider spectrum than previously believed. (PMID:15316156)
• Results show no difference in the un/folding transitions of three ataxin-3 variants, which indicates that the stability of the native conformation was not affected by polyglutamine tract extension. (PMID:15345714)
• An ataxin-3 fragment containing residues C terminal to amino acid 221 including the polyglutamine expansion is toxic to neuroblastoma cells and is found in vivo in affected brain regions. (PMID:15537899)
• Data support a mechanism in which the thermodynamic stability of ataxin-3 is governed by the properties of the Josephin domain, but the presence of an expanded polyQ tract increases dramatically the protein’s tendency to aggregate. (PMID:15544810)
• NMR structure of ataxin 3 (PMID:15630566)
• the deubiquitylating activity of AT3 and its ubiquitin interacting motifs play essential roles in CFTRDeltaF508 aggresome formation (PMID:15767577)
• Normal human ataxin-3 is a striking suppressor of polyglutamine neurodegeneration in vivo. (PMID:15808507)
• Findings suggest that the interaction of small ubiquitin-like modifier 1 with N-terminus of ataxin-3 first and the relevant sumoylation probably participate in the post-translation modifying of ataxin-3 and in the pathogenesis of SCA3/MJD. (PMID:15952105)
• Through its ubiquitin interaction motifs, normal or expanded ataxin-3 binds a broad range of ubiquitinated proteins that accumulate when the proteasome is inhibited. (PMID:16040601)
• ataxin-3 may function as a polyubiquitin chain-editing enzyme (PMID:16118278)
• cells surviving under conditions of polyglutamine cytotoxicity unfold and remove mutant ataxin-3 in presence of increased level of Hsp27 (PMID:16126176)
• VCP-Atx-3 association is a potential target for therapeutic intervention and suggest that it might influence the progression of spinocerebellar ataxia type 3. (PMID:16525503)
• ataxin-3 has an inherent capacity to aggregate through its non-polyglutamine domains (PMID:16624810)
• The main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process. (PMID:16724006)
• ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. (PMID:16791428)
• Normal function of AT3 might be to regulate flow through the ERAD pathway by modulating VCP-dependent extraction of proteins from the ER. (PMID:16822850)
• linkage and association for three CAG triplet repeat markers (Spinocerebellar Ataxia Type 1, SCA1; Machado-Joseph Disease, MJD; Dentatorubro-pallidoluysian Atrophy, DRPLA) to assess their contribution to variation in cognitive ability (PMID:16967484)
• We present evidence that atx3 may promote p97-associated deubiquitination to facilitate the transfer of polypeptides from p97 to the proteasome. (PMID:17000876)
• Normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its ubiquitin-interacting motif-associated function. (PMID:17079677)
• The N-terminus of ataxin-3, which serves as a recognition site by p45, is necessary for the proteolytic process of ataxin-3. (PMID:17302910)
• Our results imply that phosphorylation of serine 256 in ataxin-3 by GSK 3beta regulates ataxin-3 aggregation. (PMID:17434145)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	atxn3	ENSDARG00000099274
mus_musculus	Atxn3	ENSMUSG00000021189
rattus_norvegicus	Atxn3	ENSRNOG00000005470
caenorhabditis_elegans		WBGENE00006446

Paralogs (1): ATXN3L (ENSG00000123594)

Protein

Protein identifiers

Ataxin-3 — P54252 (reviewed: P54252)

Alternative names: Machado-Joseph disease protein 1, Spinocerebellar ataxia type 3 protein

All UniProt accessions (25): P54252, A0A0A0MS38, A0A2R8Y3X7, A0A2R8Y888, C9JQV6, D3VVP3, D6R9I5, E9PJN5, F5H211, G3V2G1, G3V2G2, G3V328, G3V390, G3V3A6, G3V3R7, G3V3S5, G3V3T0, G3V3T6, G3V4B1, G3V4F4, G3V4F5, G3V4U9, G3V526, G3V5H3, S4R399

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates. Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins. Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription. Acts as a negative regulator of mTORC1 signaling in response to amino acid deprivation by mediating deubiquitination of RHEB, thereby promoting RHEB inactivation by the TSC-TBC complex. Regulates autophagy via the deubiquitination of ‘Lys-402’ of BECN1 leading to the stabilization of BECN1.

Subunit / interactions. Interacts with STUB1/CHIP (when monoubiquitinated). Interacts with DNA repair proteins RAD23A and RAD23B. Interacts with BECN1 (via its poly-Gln domain). Interacts with PRKN, UBR2, VCP and tubulin. Short isoform 1 interacts with CASP7.

Subcellular location. Nucleus matrix. Nucleus. Lysosome membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Monoubiquitinated N-terminally by UBE2W, possibly leading to activate the deubiquitinating enzyme activity.

Disease relevance. Spinocerebellar ataxia 3 (SCA3) [MIM:109150] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA3 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. The molecular defect in SCA3 is the a CAG repeat expansion in ATX3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The UIM domains bind ubiquitin and interact with various E3 ubiquitin-protein ligase, such as STUB1/CHIP. They are essential to limit the length of ubiquitin chains. The poly-Gln domain is involved in the interaction with BECN1 and subsequent starvation-induced autophagy.

Polymorphism. The poly-Gln region of ATXN3 is highly polymorphic (14 to 41 repeats) in the normal population and is expanded to about 55-82 repeats in spinocerebellar ataxia 3 (SCA3) patients.

Isoforms (5)

UniProt ID	Names	Canonical?
P54252-2	2	yes
P54252-1	1, MJD1a
P54252-3	3
P54252-4	4
P54252-5	5

RefSeq proteins (9): NP_001121168, NP_001121169, NP_001158250, NP_001158251, NP_001158252, NP_001158253, NP_001410999, NP_004984, NP_109376 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003903	UIM_dom	Conserved_site
IPR006155	Josephin	Domain
IPR033865	Ataxin-3	Family

Pfam: PF02099, PF02809, PF16619

UniProt features (56 total): helix 12, strand 10, domain 4, modified residue 4, splice variant 4, mutagenesis site 4, compositionally biased region 4, active site 3, sequence variant 3, turn 3, cross-link 2, chain 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4YS9	X-RAY DIFFRACTION	2
4WTH	X-RAY DIFFRACTION	2.25
1YZB	SOLUTION NMR
2AGA	SOLUTION NMR
2DOS	SOLUTION NMR
2JRI	SOLUTION NMR
2KLZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54252-F1	76.74	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 14 (nucleophile); 119 (proton acceptor); 134

Post-translational modifications (6): 219, 265, 272, 328, 1, 200

Mutagenesis-validated functional residues (4):

Position	Phenotype
14	loss of deubiquitination activity.
236	inhibits substrate trapping.
256	inhibits substrate trapping.
335	no effect on ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5689877	Josephin domain DUBs
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-212436	Generic Transcription Pathway
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9614085	FOXO-mediated transcription

MSigDB gene sets: 0 (showing top):

GO Biological Process (30): microtubule cytoskeleton organization (GO:0000226), nucleotide-excision repair (GO:0006289), ubiquitin-dependent protein catabolic process (GO:0006511), protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), regulation of cell-substrate adhesion (GO:0010810), protein deubiquitination (GO:0016579), actin cytoskeleton organization (GO:0030036), cellular response to amino acid starvation (GO:0034198), cellular response to heat (GO:0034605), monoubiquitinated protein deubiquitination (GO:0035520), exploration behavior (GO:0035640), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), intermediate filament cytoskeleton organization (GO:0045104), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), cellular response to misfolded protein (GO:0071218), negative regulation of TORC1 signaling (GO:1904262), positive regulation of ERAD pathway (GO:1904294), protein localization to cytosolic proteasome complex (GO:1904327), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), cytoplasmic translation (GO:0002181), proteolysis (GO:0006508), cellular response to starvation (GO:0009267), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), positive regulation of TORC1 signaling (GO:1904263)

GO Molecular Function (10): cysteine-type deubiquitinase activity (GO:0004843), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), ATPase binding (GO:0051117), K63-linked deubiquitinase activity (GO:0061578), K48-linked deubiquitinase activity (GO:1990380), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (15): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear matrix (GO:0016363), mitochondrial membrane (GO:0031966), nuclear inclusion body (GO:0042405), synapse (GO:0045202), lysosome (GO:0005764), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Deubiquitination	1
FOXO-mediated transcription	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeleton organization	3
protein deubiquitination	3
deubiquitinase activity	3
nuclear lumen	3
mitochondrion	2
organelle membrane	2
microtubule-based process	1
DNA repair	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein catabolic process	1
anterograde trans-synaptic signaling	1
system development	1
regulation of cell adhesion	1
cell-substrate adhesion	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
actin filament-based process	1
cellular response to starvation	1
response to amino acid starvation	1
response to heat	1
cellular response to stress	1
behavior	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
intermediate filament-based process	1
cellular response to topologically incorrect protein	1
response to misfolded protein	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
ERAD pathway	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
cysteine-type peptidase activity	1
ubiquitin-like protein ligase binding	1
protein binding	1
enzyme binding	1

Protein interactions and networks

STRING

2034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATXN3	VCP	P55072	992
ATXN3	RAD23A	P54725	985
ATXN3	RAD23B	P54727	971
ATXN3	ITPR1	Q14643	969
ATXN3	JOSD1	Q15040	954
ATXN3	ATXN2	Q99700	939
ATXN3	UBQLN1	Q9UMX0	921
ATXN3	ATXN1	P54253	908
ATXN3	STUB1	Q9UNE7	906
ATXN3	ATXN7	O15265	895
ATXN3	HDAC6	Q9UBN7	894
ATXN3	BECN1	Q14457	867
ATXN3	PRKN	O60260	842
ATXN3	HTT	P42858	836
ATXN3	NPLOC4	Q8TAT6	801

IntAct

426 interactions, top by confidence:

A	B	Type	Score
ATXN3	VCP	psi-mi:“MI:0915”(physical association)	0.680
ATXN3	RAD23A	psi-mi:“MI:0915”(physical association)	0.670
ATXN3	EWSR1	psi-mi:“MI:0915”(physical association)	0.670
ATXN3	PHAF1	psi-mi:“MI:0915”(physical association)	0.670
ATXN3	ARHGAP19	psi-mi:“MI:0915”(physical association)	0.670
PRKACA	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
TGFBR2	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
CCT6A	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
DNM2	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
MKL1	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
PDPK1	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
SOX14	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
CASP1	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
CASP3	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
PSMD7	ATXN3	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	EWSR1	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	TERF2	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	FOXD4L6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (665): VCP (Co-fractionation), UBC (Reconstituted Complex), VCP (Reconstituted Complex), UBC (Co-crystal Structure), VCP (Co-crystal Structure), UBC (Affinity Capture-MS), SQSTM1 (Affinity Capture-Western), SQSTM1 (Reconstituted Complex), ATXN3 (Reconstituted Complex), UBC (Biochemical Activity), UBC (Reconstituted Complex), UBC (Biochemical Activity), ATXN3 (Biochemical Activity), UBC (Reconstituted Complex), ATXN3 (Affinity Capture-MS)

ESM2 similar proteins: A0JPP7, E9Q4Z2, F1N2W9, F1QDI9, O12940, O35815, O60784, O70593, O88746, O88978, O88984, O95453, P54252, P54731, P58797, P69341, Q0VGM9, Q1RMR5, Q28BP9, Q2HJD0, Q2T9Z1, Q32LM2, Q3TDN2, Q5BK32, Q5R752, Q5RC51, Q5RJZ1, Q68FJ8, Q6AZH6, Q6GQ69, Q6H1L8, Q6R005, Q6TH22, Q7ZU92, Q7ZYA7, Q80W98, Q8BJU0, Q8CFK2, Q8UUU2, Q8VD33

Diamond homologs: O17850, O35815, P54252, Q60XN1, Q8LQ36, Q9CVD2, Q9H3M9, Q9M391, Q9W689, Q8TAC2, Q9CR30

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
GSK3B	“up-regulates quantity by stabilization”	ATXN3	phosphorylation
UBE4B	“down-regulates quantity by destabilization”	ATXN3	polyubiquitination
CSNK2A1	“up-regulates activity”	ATXN3	phosphorylation
STUB1	“down-regulates quantity by destabilization”	ATXN3	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

110 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	49
Likely benign	11
Benign	13

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
209995	NM_004993.5(ATXN3):c.886_888CAG(60_86) (p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln)	Pathogenic
3780671	NM_004993.6(ATXN3):c.916_917insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC (p.Gly306fs)	Likely pathogenic

SpliceAI

2464 predictions. Top by Δscore:

Variant	Effect	Δscore
14:92064329:T:A	donor_gain	1.0000
14:92070929:CCTTA:C	donor_loss	1.0000
14:92070930:CTTA:C	donor_loss	1.0000
14:92070931:TTAC:T	donor_loss	1.0000
14:92070932:TA:T	donor_loss	1.0000
14:92070933:A:T	donor_loss	1.0000
14:92071050:CTGT:C	acceptor_gain	1.0000
14:92071051:TGT:T	acceptor_gain	1.0000
14:92071053:TC:T	acceptor_loss	1.0000
14:92071054:C:CA	acceptor_loss	1.0000
14:92071054:C:CC	acceptor_gain	1.0000
14:92079413:A:AC	donor_gain	1.0000
14:92079414:C:CC	donor_gain	1.0000
14:92079470:T:C	acceptor_gain	1.0000
14:92080945:A:C	donor_gain	1.0000
14:92080956:CTA:C	donor_gain	1.0000
14:92080959:CTTTA:C	donor_gain	1.0000
14:92080963:A:AC	donor_gain	1.0000
14:92080964:C:CC	donor_gain	1.0000
14:92081058:CTAC:C	acceptor_gain	1.0000
14:92081059:TAC:T	acceptor_gain	1.0000
14:92081060:AC:A	acceptor_gain	1.0000
14:92081061:CC:C	acceptor_gain	1.0000
14:92081062:C:CC	acceptor_gain	1.0000
14:92081062:CTGAA:C	acceptor_loss	1.0000
14:92082295:TTTAC:T	donor_loss	1.0000
14:92082296:TTA:T	donor_loss	1.0000
14:92082297:TACCT:T	donor_loss	1.0000
14:92082298:A:AT	donor_loss	1.0000
14:92082299:C:CT	donor_loss	1.0000

AlphaMissense

2391 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:92083235:C:G	G167R	1.000
14:92083240:A:T	V165D	1.000
14:92083243:A:T	V164D	1.000
14:92083245:A:C	F163L	1.000
14:92083245:A:T	F163L	1.000
14:92083246:A:C	F163C	1.000
14:92083246:A:G	F163S	1.000
14:92083247:A:G	F163L	1.000
14:92083247:A:T	F163I	1.000
14:92083249:A:C	I162R	1.000
14:92083249:A:T	I162K	1.000
14:92083253:A:G	S161P	1.000
14:92083256:A:C	Y160D	1.000
14:92088741:A:G	L155S	1.000
14:92088744:T:G	Q154P	1.000
14:92088748:C:G	A153P	1.000
14:92088750:A:G	L152S	1.000
14:92088752:G:C	F151L	1.000
14:92088752:G:T	F151L	1.000
14:92088753:A:G	F151S	1.000
14:92088754:A:G	F151L	1.000
14:92088756:A:G	L150P	1.000
14:92088762:A:G	L148P	1.000
14:92088762:A:T	L148H	1.000
14:92088766:A:C	Y147D	1.000
14:92088777:A:T	I143K	1.000
14:92088786:G:T	P140Q	1.000
14:92088798:A:G	L136P	1.000
14:92088801:G:A	S135F	1.000
14:92088802:A:G	S135P	1.000

dbSNP variants (sampled 300 via entrez): RS1000075222 (14:92081721 A>G), RS1000145307 (14:92104791 C>T), RS1000302050 (14:92089958 C>A), RS1000321907 (14:92067833 A>C,T), RS1000337986 (14:92068877 A>C), RS1000513663 (14:92076825 A>G), RS1000530021 (14:92091593 T>C), RS1000569078 (14:92090304 C>T), RS1000625978 (14:92070655 G>A), RS1000653550 (14:92097583 T>C), RS1000828962 (14:92074062 C>T), RS1000832889 (14:92102241 G>A), RS1000930611 (14:92099248 C>T), RS1000942240 (14:92079390 T>C), RS1000967846 (14:92077177 A>G)

Disease associations

OMIM: gene MIM:607047 | disease phenotypes: MIM:109150, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
Machado-Joseph disease	Definitive	Autosomal dominant
Machado-Joseph disease type 1	Supportive	Autosomal dominant
Machado-Joseph disease type 2	Supportive	Autosomal dominant
Machado-Joseph disease type 3	Supportive	Autosomal dominant

Mondo (5): Machado-Joseph disease (MONDO:0007182), late-onset Parkinson disease (MONDO:0008199), Machado-Joseph disease type 1 (MONDO:0017174), Machado-Joseph disease type 2 (MONDO:0017175), Machado-Joseph disease type 3 (MONDO:0017176)

Orphanet (2): Spinocerebellar ataxia type 3 (Orphanet:98757), Hereditary late-onset Parkinson disease (Orphanet:411602)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000012	Urinary urgency
HP:0000298	Mask-like facies
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000544	External ophthalmoplegia
HP:0000590	Progressive external ophthalmoplegia
HP:0000623	Supranuclear ophthalmoplegia
HP:0000640	Gaze-evoked nystagmus
HP:0000641	Dysmetric saccades
HP:0000651	Diplopia
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0001151	Impaired horizontal smooth pursuit
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001605	Vocal cord paralysis
HP:0001621	Weak voice
HP:0001751	Abnormal vestibular function
HP:0002015	Dysphagia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000175_32	Height	1.000000e-10
GCST000176_15	Height	6.000000e-10
GCST001442_16	Orofacial clefts	6.000000e-06
GCST002097_1	Coronary artery calcification	9.000000e-06
GCST005647_9	Amyotrophic lateral sclerosis	3.000000e-07
GCST009614_3	LDL cholesterol levels x loop diuretics use interaction	4.000000e-07
GCST009616_4	HDL cholesterol levels x thiazide or thiazide-like diuretics use interaction	3.000000e-07
GCST010002_158	Refractive error	4.000000e-24
GCST012226_358	Waist circumference adjusted for body mass index	3.000000e-10
GCST012226_359	Waist circumference adjusted for body mass index	1.000000e-11
GCST90020028_1874	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017827	Machado-Joseph Disease	C10.228.140.252.190.530.530; C10.228.140.252.700.700.500; C10.228.854.787.875.500; C10.574.500.825.700.500; C10.597.350.090.500.530.530; C16.320.400.780.875.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523240 (SINGLE PROTEIN), CHEMBL6193783 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression, affects binding, decreases activity, increases activity	2
Cisplatin	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Rotenone	decreases expression, increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
beta-N-methylamino-L-alanine	increases expression	1
methylmercuric chloride	increases expression, decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
salinomycin	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
dinophysistoxin 1	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CPG-oligonucleotide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Decitabine	affects expression	1
Acrolein	affects cotreatment, decreases expression	1
Aluminum	affects folding, affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Cocaine	decreases expression	1
Demecolcine	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4358862	Binding	Inhibition of human recombinant Ataxin-3 assessed as reduction in cleavage of luminescent substrate Ub-AML at 100 uM	Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs. — J Med Chem

Cellosaurus cell lines

40 cell lines: 32 induced pluripotent stem cell, 3 finite cell line, 2 cancer cell line, 2 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_7451	GM06151	Finite cell line	Male
CVCL_7452	GM06153	Finite cell line	Male
CVCL_A0SP	HEK293T ATXN3 KO	Transformed cell line	Female
CVCL_A0SQ	U2OS ATXN3 KO	Cancer cell line	Female
CVCL_A3ZM	ZZUi026-A	Induced pluripotent stem cell	Male
CVCL_A4GP	CSUXHi005-A	Induced pluripotent stem cell	Female
CVCL_C0IB	GZHMCi009-A	Induced pluripotent stem cell	Male
CVCL_C0IC	GZHMCi010-A	Induced pluripotent stem cell	Female
CVCL_C0KB	AIW002-02/ATXN3-KO	Induced pluripotent stem cell	Male
CVCL_C9HT	ZZUi037-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

42 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT00992771	PHASE2	COMPLETED	Study to Determine the Safety and Tolerability of Varenicline (Chantix®) in Treating Spinocerebellar Ataxia Type 3
NCT01096095	PHASE2	WITHDRAWN	Pilot Study of Safety and Efficacy of Sodium Phenylbutyrate in Spinocerebellar Ataxia Type 3
NCT02039206	PHASE2	COMPLETED	The Influence of Deep TMS on Cerebellar Signs in Patients With Machado Joseph Disease
NCT02147886	PHASE2	COMPLETED	Study To Assess Safety, Tolerability and Efficacy of Intravenous Cabaletta in Patients With Machado-Joseph Disease
NCT03378414	PHASE2	NOT_YET_RECRUITING	Umbilical Cord Mesenchymal Stem Cells Therapy (19#iSCLife®-SA) for Patients With Spinocerebellar Ataxia
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05160558	PHASE1	TERMINATED	A Pharmacokinetics and Safety Study of BIIB132 in Adults With Spinocerebellar Ataxia 3
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT01096082	PHASE2/PHASE3	COMPLETED	Safety and Efficacy of Lithium Carbonate in Patients With Spinocerebellar Ataxia Type 3
NCT05490563	PHASE2/PHASE3	TERMINATED	STRIDES - a Clinical Research Study of an Investigational New Drug to Treat Spinocerebellar Ataxia
NCT05822908	PHASE1/PHASE2	RECRUITING	A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD
NCT01060371	Not specified	UNKNOWN	Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02175290	Not specified	UNKNOWN	Machado-Joseph Disease in Israel
NCT02906046	Not specified	COMPLETED	Weight in Lower Limbs Improves Gait Ataxia of in Machado-Joseph Disease Patients
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia
NCT03487367	Not specified	UNKNOWN	Clinical Trial Readiness for SCA1 and SCA3
NCT03885167	Not specified	COMPLETED	Identification of Biomarkers in Spinocerebellar Ataxia 3
NCT04153110	Not specified	COMPLETED	Cerebello-Spinal tDCS as Rehabilitative Intervention in Neurodegenerative Ataxia
NCT04229823	Not specified	UNKNOWN	Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD
NCT04268147	Not specified	COMPLETED	Instrumented Data Exchange for Ataxia Study
NCT04399265	Not specified	UNKNOWN	Efficacy Of Oral Trehalose In Spinocerebellar Ataxia 3
NCT04419974	Not specified	UNKNOWN	Astrocytic Markers and the Pre-ataxic Period of SCA3/MJD - BIGPRO Study Astrocytes
NCT04426149	Not specified	COMPLETED	Clinical Effects of Oral Trehalose In Patients With Spinocerebellar Ataxia 3
NCT04714307	Not specified	UNKNOWN	Neuropsychiatry and Cognition in SCA3/MJD
NCT05486806	Not specified	UNKNOWN	Longitudinal Tracking of Patients Diagnosed With Neurodegenerative Movement Disorders
NCT05502432	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation in SCA3 Patients
NCT05557786	Not specified	COMPLETED	Treatment of Transcranial Alternating Current Stimulation（tACS）on Cerebellar Ataxia
NCT05826171	Not specified	ACTIVE_NOT_RECRUITING	Priming Motor Learning Through Exercise in People With Spinocerebellar Ataxia
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease