Details of Disease

General Information of Disease (ID: DISQBQID)

Disease Name	Spinocerebellar ataxia type 3
Synonyms	spinocerebellar atrophy type 3; Spinopontine atrophy; Nigrospinodentatal Degeneration; spinocerebellar atrophy 3; Azorean neurologic disease; spinocerebellar ataxia 3; Azorean disease of the nervous system; Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia; autosomal dominant striatonigral degeneration; SCA3; Machado-Joseph disease; Machado disease; spinocerebellar ataxia type 3; Azorean disease; MJD
Disease Class	8A03: Ataxic disorder
Definition	Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations.
Disease Hierarchy	DIS947AF: Autosomal dominant cerebellar ataxia type I DIS6BW88: Huntington disease-like syndrome DISQBQID: Spinocerebellar ataxia type 3
ICD Code	ICD-11 ICD-11: 8A03.16
Disease Identifiers	MONDO ID MONDO_0007182 MESH ID D017827 UMLS CUI C0024408 OMIM ID 109150 MedGen ID 9841 Orphanet ID 98757 SNOMED CT ID 91952008

Drug-Interaction Atlas (DIA) of This Disease

Drug-Interaction Atlas (DIA)

This Disease is Treated as An Indication in 2 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
BIIB132	DMUJ0EL	Phase 1	Antisense oligonucleotide	[1]
ION260	DMR2RFL	Phase 1	Antisense oligonucleotide	[2]
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Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 16 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
ARSB	TTESQTG	Limited	Biomarker	[3]
ASIC1	TTRJYB6	Limited	Biomarker	[4]
DMPK	TTZQTY2	Limited	Biomarker	[5]
DNMT3L	TT3FDAV	Limited	Genetic Variation	[6]
HMBS	TTT0HW3	Limited	Biomarker	[7]
PNKP	TTHR3IE	Limited	Genetic Variation	[8]
TDO2	TTXNCBV	Limited	Altered Expression	[9]
TOR1A	TTF85KW	Limited	Genetic Variation	[10]
CACNA1A	TTX4QDJ	Strong	Biomarker	[11]
DNAJB1	TTPXAWS	Strong	Biomarker	[12]
HTT	TTIWZ0O	Strong	Biomarker	[13]
SLC18A2	TTNZRI3	Strong	Genetic Variation	[10]
TH	TTUHP71	Strong	Biomarker	[14]
VCP	TTHNLSB	Strong	Biomarker	[15]
ZUP1	TTZC0KV	Strong	Genetic Variation	[16]
ATXN3	TT6A17J	Definitive	Autosomal dominant	[17]
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⏷ Show the Full List of 16 DTT(s)

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
FXN	DEXVHDB	moderate	Biomarker	[18]
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This Disease Is Related to 40 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ACY3	OTZWAB73	Limited	Altered Expression	[19]
ATG12	OTJRO09Y	Limited	Altered Expression	[20]
ATG16L2	OTJYU0W8	Limited	Altered Expression	[20]
CA11	OT8RX3AJ	Limited	Biomarker	[21]
CA8	OT9Y8GA8	Limited	Biomarker	[22]
CAST	OTBXZZGF	Limited	Biomarker	[23]
CFDP1	OTXY7J96	Limited	Biomarker	[24]
CTRL	OTB6NA5O	Limited	Altered Expression	[25]
CUL1	OTXPE1UZ	Limited	Altered Expression	[26]
EFNA3	OTJGOUMZ	Limited	Altered Expression	[27]
EIF4G2	OTEO98CR	Limited	Biomarker	[24]
ELAVL3	OTI2VI8B	Limited	Biomarker	[28]
FBXO33	OTENSSJD	Limited	Biomarker	[26]
FOXO4	OT90X9LN	Limited	Biomarker	[29]
GABARAP	OTAQUX6E	Limited	Biomarker	[30]
HSPBP1	OTRS37HK	Limited	Biomarker	[31]
ND1	OTCLGIXV	Limited	Biomarker	[32]
ND4	OT4RQVAA	Limited	Altered Expression	[32]
PICK1	OT8QE6EU	Limited	Biomarker	[33]
PLEKHG4	OT3RBPFL	Limited	Genetic Variation	[34]
POU2F2	OTPV0J0C	Limited	Biomarker	[35]
PSMD2	OT6HZHN7	Limited	Biomarker	[24]
RAB1A	OTKPHRD0	Limited	Biomarker	[20]
RANGAP1	OTZGD3LJ	Limited	Genetic Variation	[36]
SKP1	OT5BPAZ4	Limited	Biomarker	[37]
SPTBN2	OTDMJ75N	Limited	Genetic Variation	[34]
TMC3	OTSXYLTH	Limited	Biomarker	[38]
PPP1R1B	OTSIJMQ9	moderate	Biomarker	[14]
ATXN1	OTQF0HNR	Strong	Biomarker	[39]
ATXN10	OTKRDUNN	Strong	Biomarker	[40]
BEAN1	OT0WLH27	Strong	Biomarker	[41]
LY6E	OTMG16BZ	Strong	Genetic Variation	[42]
TAF4	OTPIRFEF	Strong	Biomarker	[43]
TBP	OT6C0S52	Strong	Altered Expression	[44]
TK2	OTS1V4XB	Strong	Biomarker	[41]
ATXN3	OTJVVGKT	Definitive	Autosomal dominant	[17]
ATXN7	OTL3YF1H	Definitive	Biomarker	[44]
IVL	OT4VPNGY	Definitive	Genetic Variation	[45]
KPNA3	OTLI3TM2	Definitive	Biomarker	[46]
SNAP29	OTT30ZON	Definitive	Biomarker	[47]
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⏷ Show the Full List of 40 DOT(s)

References

1	ClinicalTrials.gov (NCT05160558) A Phase 1, Blinded, Randomized, Placebo-controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of BIIB132 Administered Intrathecally to Adults With Spinocerebellar Ataxia 3. U.S.National Institutes of Health.
2	Clinical pipeline report, company report or official report of Ionis
3	Population medical genetics: translating science to the community.Genet Mol Biol. 2019;42(1 suppl 1):312-320. doi: 10.1590/1678-4685-GMB-2018-0096. Epub 2019 Apr 11.
4	Research on screening and identification of proteins interacting with ataxin-3.Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005 Jun;22(3):242-7.
5	Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient.Clin Neurol Neurosurg. 2009 Dec;111(10):791-4. doi: 10.1016/j.clineuro.2009.07.016. Epub 2009 Aug 26.
6	Polymorphisms in DNA methylation-related genes are linked to the phenotype of Machado-Joseph disease.Neurobiol Aging. 2019 Mar;75:225.e1-225.e8. doi: 10.1016/j.neurobiolaging.2018.11.002. Epub 2018 Nov 16.
7	Pharmacological Therapies for Machado-Joseph Disease.Adv Exp Med Biol. 2018;1049:369-394. doi: 10.1007/978-3-319-71779-1_19.
8	The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis.PLoS Genet. 2015 Jan 29;11(1):e1004749. doi: 10.1371/journal.pgen.1004749. eCollection 2015 Jan.
9	n-Butylidenephthalide exhibits protection against neurotoxicity through regulation of tryptophan 2, 3 dioxygenase in spinocerebellar ataxia type 3.Neuropharmacology. 2017 May 1;117:434-446. doi: 10.1016/j.neuropharm.2017.02.014. Epub 2017 Feb 20.
10	Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike.J Korean Med Sci. 2018 May 24;33(28):e184. doi: 10.3346/jkms.2018.33.e184. eCollection 2018 Jul 9.
11	Sequence configuration of spinocerebellar ataxia type 8 repeat expansions in a Japanese cohort of 797 ataxia subjects.J Neurol Sci. 2017 Nov 15;382:87-90. doi: 10.1016/j.jns.2017.08.3256. Epub 2017 Aug 31.
12	Upregulation of miR-370 and miR-543 is associated with reduced expression of heat shock protein 40 in spinocerebellar ataxia type 3.PLoS One. 2018 Aug 7;13(8):e0201794. doi: 10.1371/journal.pone.0201794. eCollection 2018.
13	Polyglutamine tracts regulate beclin 1-dependent autophagy.Nature. 2017 May 4;545(7652):108-111. doi: 10.1038/nature22078. Epub 2017 Apr 26.
14	Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease.Hum Mol Genet. 2008 Jul 15;17(14):2071-83. doi: 10.1093/hmg/ddn106. Epub 2008 Apr 1.
15	Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster.Neurobiol Dis. 2018 Aug;116:78-92. doi: 10.1016/j.nbd.2018.04.013. Epub 2018 Apr 26.
16	The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability.Hum Mol Genet. 2011 Jan 1;20(1):141-54. doi: 10.1093/hmg/ddq452. Epub 2010 Oct 11.
17	The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
18	Association between restless legs syndrome and other movement disorders.Neurology. 2019 May 14;92(20):948-964. doi: 10.1212/WNL.0000000000007500. Epub 2019 Apr 19.
19	Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes.Hum Mol Genet. 2017 Sep 1;26(17):3362-3374. doi: 10.1093/hmg/ddx224.
20	Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients.Neuropathology. 2018 Apr;38(2):113-124. doi: 10.1111/neup.12433. Epub 2017 Dec 8.
21	Altered expression of carbonic anhydrase-related protein XI in neuronal cells expressing mutant ataxin-3.Cerebellum. 2013 Jun;12(3):338-49. doi: 10.1007/s12311-012-0430-2.
22	Protective roles of carbonic anhydrase 8 in Machado-Joseph Disease.J Neurosci Res. 2019 Oct;97(10):1278-1297. doi: 10.1002/jnr.24474. Epub 2019 Jun 3.
23	Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease.Hum Mol Genet. 2014 Sep 15;23(18):4932-44. doi: 10.1093/hmg/ddu209. Epub 2014 May 9.
24	Imbalances in p97 co-factor interactions in human proteinopathy.EMBO Rep. 2010 Jun;11(6):479-85. doi: 10.1038/embor.2010.49. Epub 2010 Apr 23.
25	T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse.Neuropharmacology. 2015 Dec;99:308-17. doi: 10.1016/j.neuropharm.2015.08.009. Epub 2015 Aug 6.
26	FipoQ/FBXO33, a Cullin-1-based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein.J Neurochem. 2019 Jun;149(6):781-798. doi: 10.1111/jnc.14669. Epub 2019 Feb 28.
27	Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways.PLoS One. 2018 Sep 19;13(9):e0204438. doi: 10.1371/journal.pone.0204438. eCollection 2018.
28	Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein.Cell Mol Neurobiol. 2018 Apr;38(3):641-655. doi: 10.1007/s10571-017-0513-1. Epub 2017 Jun 30.
29	FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.Hum Mol Genet. 2011 Aug 1;20(15):2928-41. doi: 10.1093/hmg/ddr197. Epub 2011 May 2.
30	The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy.Aging Cell. 2020 Jan;19(1):e13051. doi: 10.1111/acel.13051. Epub 2019 Oct 17.
31	Carboxyl Terminus of Hsp70-Interacting Protein Is Increased in Serum and Cerebrospinal Fluid of Patients With Spinocerebellar Ataxia Type 3.Front Neurol. 2019 Oct 15;10:1094. doi: 10.3389/fneur.2019.01094. eCollection 2019.
32	Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease.Mol Neurobiol. 2019 Jan;56(1):119-124. doi: 10.1007/s12035-018-1069-x. Epub 2018 Apr 21.
33	Protein interacting with C kinase (PICK1) is a suppressor of spinocerebellar ataxia 3-associated neurodegeneration in Drosophila.Hum Mol Genet. 2012 Jan 1;21(1):76-84. doi: 10.1093/hmg/ddr439. Epub 2011 Sep 23.
34	Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1.Hum Mol Genet. 1995 Aug;4(8):1441-5. doi: 10.1093/hmg/4.8.1441.
35	Dopamine transporter concentration is reduced in asymptomatic Machado-Joseph disease gene carriers.J Nucl Med. 2002 Feb;43(2):153-9.
36	Segregation distortion of wild-type alleles at the Machado-Joseph disease locus: a study in normal families from the Azores islands (Portugal).J Hum Genet. 2008;53(4):333-339. doi: 10.1007/s10038-008-0261-7. Epub 2008 Feb 20.
37	Dysregulation of core components of SCF complex in poly-glutamine disorders.Cell Death Dis. 2012 Nov 22;3(11):e428. doi: 10.1038/cddis.2012.166.
38	Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model.Mol Neurodegener. 2018 Jun 22;13(1):31. doi: 10.1186/s13024-018-0261-9.
39	Suppression of Mutant Protein Expression in SCA3 and SCA1 Mice Using a CAG Repeat-Targeting Antisense Oligonucleotide.Mol Ther Nucleic Acids. 2019 Sep 6;17:601-614. doi: 10.1016/j.omtn.2019.07.004. Epub 2019 Jul 19.
40	Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal.Eur J Neurol. 2010 Jan;17(1):124-8. doi: 10.1111/j.1468-1331.2009.02757.x. Epub 2009 Jul 29.
41	Impaired Adaptive Motor Learning Is Correlated With Cerebellar Hemispheric Gray Matter Atrophy in Spinocerebellar Ataxia Patients: A Voxel-Based Morphometry Study.Front Neurol. 2019 Nov 14;10:1183. doi: 10.3389/fneur.2019.01183. eCollection 2019.
42	Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population.Brain Behav. 2019 Oct;9(10):e01414. doi: 10.1002/brb3.1414. Epub 2019 Sep 16.
43	Pathology of CAG repeat diseases.Neuropathology. 2000 Dec;20(4):319-25. doi: 10.1046/j.1440-1789.2000.00354.x.
44	Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.Brain. 2014 Sep;137(Pt 9):2444-55. doi: 10.1093/brain/awu174. Epub 2014 Jun 26.
45	Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system.Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14580-5. doi: 10.1073/pnas.93.25.14580.
46	Karyopherin -3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3.Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2624-E2633. doi: 10.1073/pnas.1716071115. Epub 2018 Feb 23.
47	Diverse mechanisms of autophagy dysregulation and their therapeutic implications: does the shoe fit?.Autophagy. 2019 Feb;15(2):368-371. doi: 10.1080/15548627.2018.1509609. Epub 2018 Sep 13.