Ataxin 1

Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.^[5][6]

ATXN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OA8, 4APT, 4AQP, 4J2J, 4J2L, 2M41
Identifiers
Aliases	ATXN1, ATX1, D6S504E, SCA1, ataxin 1
External IDs	OMIM: 601556; MGI: 104783; HomoloGene: 281; GeneCards: ATXN1; OMA:ATXN1 - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p22.3 Start 16,299,112 bp[1] End 16,761,491 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 A5|13 21.98 cM Start 45,703,231 bp[2] End 46,118,484 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell Brodmann area 23 Skeletal muscle tissue of rectus abdominis germinal epithelium orbitofrontal cortex Brodmann area 46 epithelium of colon biceps brachii Skeletal muscle tissue of biceps brachii cartilage tissue Top expressed in dorsal striatum medial dorsal nucleus lateral geniculate nucleus medial geniculate nucleus olfactory tubercle lateral septal nucleus parotid gland nucleus accumbens temporal muscle triceps brachii muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function poly(G) binding protein self-association DNA binding RNA binding protein C-terminus binding protein binding identical protein binding poly(U) RNA binding Cellular component cytoplasm nuclear matrix nuclear inclusion body nuclear RNA export factor complex nucleus nucleoplasm nucleolus cytosol Biological process nuclear export RNA processing negative regulation of transcription, DNA-templated regulation of transcription, DNA-templated transcription, DNA-templated brain development learning memory social behavior negative regulation of transcription by RNA polymerase II lung alveolus development nervous system development anatomical structure development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6310 20238 Ensembl ENSG00000124788 ENSMUSG00000046876 UniProt P54253 P54254 RefSeq (mRNA) NM_001128164 NM_000332 NM_001357857 NM_001199304 NM_001199305 NM_009124 RefSeq (protein) NP_000323 NP_001121636 NP_001344786 NP_001186233 NP_001186234 NP_033150 Location (UCSC) Chr 6: 16.3 – 16.76 Mb Chr 13: 45.7 – 46.12 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mutations in ataxin-1 cause spinocerebellar ataxia type 1, an inherited neurodegenerative disease characterized by a progressive loss of cerebellar neurons, particularly Purkinje neurons.

Genetics

ATXN1 is conserved across multiple species, including humans, mice, and Drosophila.^[7]

In humans, ATXN1 is located on the short arm of chromosome 6. The gene contains 9 exons, two of which are protein-coding. There is a CAG repeat in the coding sequence which is longer in humans than other species (6-38 uninterrupted CAG repeats in healthy humans versus 2 in the mouse gene). This repeat is prone to errors in DNA replication and can vary widely in length between individuals.^[8]

Structure

Notable features of the Ataxin-1 protein structure^[9] include:

• A polyglutamine tract of variable length, encoded by the CAG repeat in ATXN1.
• A region which mediates protein-protein interactions, known as the AXH domain
• A nuclear localization sequence
• A phosphorylation site which regulates the protein's stability and interactions with its binding partners

Function

The function of Ataxin-1 is not completely understood. It appears to be involved in regulating gene expression based on its location in the nucleus of the cell, its association with promoter regions of several genes, and its interactions with transcriptional regulators^[10] and parts of the RNA splicing machinery.^[11]

Interactions

Ataxin 1 has been shown to interact with:

• C2orf27,^[12]
• Coilin,^[13][14]
• Glyceraldehyde 3-phosphate dehydrogenase,^[15]
• CIC^[16][17]
• UBE2E1,^[14] and
• USP7.^[18]

Role in disease

ATXN1 is the gene mutated in spinocerebellar ataxia type 1 (SCA1), a dominantly-inherited, fatal genetic disease in which neurons in the cerebellum and brain stem degenerate over the course of years or decades.^[8] SCA1 is a trinucleotide repeat disorder caused by expansion of the CAG repeat in ATXN1; this leads to an expanded polyglutamine tract in the protein. This elongation is variable in length, with as few as 6 and as many as 81 repeats reported in humans.^[19][8] Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression.^[20]

How polyglutamine expansion in Ataxin-1 causes neuronal dysfunction and degeneration is still unclear. Disease likely occurs through the combination of several processes.

Aggregation

Mutant Ataxin-1 protein spontaneously misfolds and forms aggregates in cells,^[21] much like other disease-associated proteins such as tau, Aβ, and huntingtin. This led to the hypothesis that the aggregates are toxic to neurons, but it has been shown in mice that aggregation is not required for pathogenesis.^[22] Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.^[23]

^{[24] [25] [26] [27] [28] [29]}

Altered protein-protein interactions

Soluble Ataxin-1 interacts with many other proteins. Polyglutamine expansion in Ataxin-1 can affect these interactions, sometimes causing loss of function (where the protein fails to perform one of its normal functions) and sometimes causing toxic gain of function (where the protein binds too strongly or to an inappropriate target).^[30] This, in turn, could alter the expression of the genes ataxin-1 regulates, leading to disease.

HMGB1 interaction

Mutant ataxin1 causes the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). In a mouse model of SCA1, mutant ataxin1 mediates the reduction or inhibition of the high mobility group box1 protein (HMGB1) in neuron mitochondria.^[31] HMGB1 is a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. The impairment of HMGB1 function leads to increased mitochondrial DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitates repair of the mitochondrial DNA damage, ameliorates the neuropathology and the motor deficits, and extends the lifespan of these mutant ataxin1 mice.^[31]

References

1. GRCh38: Ensembl release 89: ENSG00000124788 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000046876 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Volz A, Fonatsch C, Ziegler A (Jun 1992). "Regional mapping of the gene for autosomal dominant spinocerebellar ataxia (SCA1) by localizing the closely linked D6S89 locus to 6p24.2----p23.05". Cytogenetics and Cell Genetics. 60 (1): 37–9. doi:10.1159/000133291. PMID 1582256.
6. "Entrez Gene: ATXN1 ataxin 1".
7. "Atx-1 - Ataxin 1 - Drosophila melanogaster (Fruit fly) - Atx-1 gene & protein". www.uniprot.org. Retrieved 2018-01-11.
8. Orr HT, Chung MY, Banfi S, Kwiatkowski TJ, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY (July 1993). "Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1". Nature Genetics. 4 (3): 221–6. doi:10.1038/ng0793-221. PMID 8358429. S2CID 8877695.
9. Zoghbi HY, Orr HT (March 2009). "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1". The Journal of Biological Chemistry. 284 (12): 7425–9. doi:10.1074/jbc.r800041200. PMC 2658037. PMID 18957430.
10. Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY (December 2006). "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology". Cell. 127 (7): 1335–47. doi:10.1016/j.cell.2006.11.038. PMID 17190598. S2CID 14900395.
11. Kim E, Lee Y, Choi S, Song JJ (July 2014). "Structural basis of the phosphorylation dependent complex formation of neurodegenerative disease protein Ataxin-1 and RBM17". Biochemical and Biophysical Research Communications. 449 (4): 399–404. doi:10.1016/j.bbrc.2014.05.063. PMID 24858692.
12. Suter B, Fontaine JF, Yildirimman R, Raskó T, Schaefer MH, Rasche A, Porras P, Vázquez-Álvarez BM, Russ J, Rau K, Foulle R, Zenkner M, Saar K, Herwig R, Andrade-Navarro MA, Wanker EE (2013). "Development and application of a DNA microarray-based yeast two-hybrid system". Nucleic Acids Research. 41 (3): 1496–507. doi:10.1093/nar/gks1329. PMC 3561971. PMID 23275563.
13. Hong S, Ka S, Kim S, Park Y, Kang S (May 2003). "p80 coilin, a coiled body-specific protein, interacts with ataxin-1, the SCA1 gene product". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1638 (1): 35–42. doi:10.1016/s0925-4439(03)00038-3. PMID 12757932.
14. Hong S, Lee S, Cho SG, Kang S (June 2008). "UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1". Biochemical and Biophysical Research Communications. 371 (2): 256–60. doi:10.1016/j.bbrc.2008.04.066. PMID 18439907.
15. Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY (September 1996). "Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase". Human Molecular Genetics. 5 (9): 1311–8. doi:10.1093/hmg/5.9.1311. PMID 8872471.
16. Lee Y (April 2020). "Regulation and function of capicua in mammals". Experimental & Molecular Medicine. 52 (4): 531–537. doi:10.1038/s12276-020-0411-3. PMC 7210929. PMID 32238859.
17. Lu HC, Tan Q, Rousseaux MW, Wang W, Kim JY, Richman R, Wan YW, Yeh SY, Patel JM, Liu X, Lin T, Lee Y, Fryer JD, Han J, Chahrour M, Finnell RH, Lei Y, Zurita-Jimenez ME, Ahimaz P, Anyane-Yeboa K, Van Maldergem L, Lehalle D, Jean-Marcais N, Mosca-Boidron AL, Thevenon J, Cousin MA, Bro DE, Lanpher BC, Klee EW, Alexander N, Bainbridge MN, Orr HT, Sillitoe RV, Ljungberg MC, Liu Z, Schaaf CP, Zoghbi HY (April 2017). "Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans". Nature Genetics. 49 (4): 527–536. doi:10.1038/ng.3808. PMC 5374026. PMID 28288114.
18. Hong S, Kim SJ, Ka S, Choi I, Kang S (June 2002). "USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product". Molecular and Cellular Neurosciences. 20 (2): 298–306. doi:10.1006/mcne.2002.1103. PMID 12093161. S2CID 41295664.
19. Matilla T, Volpini V, Genís D, Rosell J, Corral J, Dávalos A, Molins A, Estivill X (December 1993). "Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias". Human Molecular Genetics. 2 (12): 2123–8. doi:10.1093/hmg/2.12.2123. PMID 8111382.
20. Donato SD, Mariotti C, Taroni F (2012-01-01). "Spinocerebellar ataxia type 1". In Dürr SH (ed.). Handbook of Clinical Neurology. Ataxic Disorders. Vol. 103. Elsevier. pp. 399–421. doi:10.1016/B978-0-444-51892-7.00025-5. ISBN 9780444518927. PMID 21827903. S2CID 68966133.
21. Shastry BS (July 2003). "Neurodegenerative disorders of protein aggregation". Neurochemistry International. 43 (1): 1–7. doi:10.1016/s0197-0186(02)00196-1. PMID 12605877. S2CID 31191916.
22. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT (1998). "Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice". Cell. 95 (1): 41–53. doi:10.1016/s0092-8674(00)81781-x. PMID 9778246. S2CID 638016.
23. Petrakis S, Raskó T, Russ J, Friedrich RP, Stroedicke M, Riechers SP, et al. (Aug 2012). "Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1". PLOS Genetics. 8 (8): e1002897. doi:10.1371/journal.pgen.1002897. PMC 3420947. PMID 22916034.
24. Al-Ramahi I, Lam YC, Chen HK, de Gouyon B, Zhang M, Pérez AM, Branco J, de Haro M, Patterson C, Zoghbi HY, Botas J (September 2006). "CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation". The Journal of Biological Chemistry. 281 (36): 26714–24. doi:10.1074/jbc.M601603200. PMID 16831871.
25. de Chiara C, Menon RP, Dal Piaz F, Calder L, Pastore A (December 2005). "Polyglutamine is not all: the functional role of the AXH domain in the ataxin-1 protein". Journal of Molecular Biology. 354 (4): 883–93. doi:10.1016/j.jmb.2005.09.083. PMID 16277991.
26. Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY (August 2005). "The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins". Cell. 122 (4): 633–44. doi:10.1016/j.cell.2005.06.012. PMID 16122429. S2CID 16706329.
27. Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, Tsai CC (September 2005). "Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1". The EMBO Journal. 24 (18): 3339–51. doi:10.1038/sj.emboj.7600785. PMC 1224676. PMID 16121196.
28. Park Y, Hong S, Kim SJ, Kang S (February 2005). "Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product". Molecules and Cells. 19 (1): 23–30. doi:10.1016/S1016-8478(23)13132-3. PMID 15750336.
29. Irwin S, Vandelft M, Pinchev D, Howell JL, Graczyk J, Orr HT, Truant R (January 2005). "RNA association and nucleocytoplasmic shuttling by ataxin-1". Journal of Cell Science. 118 (Pt 1): 233–42. doi:10.1242/jcs.01611. PMID 15615787. S2CID 14401082.
30. Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY (April 2008). "Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1". Nature. 452 (7188): 713–8. Bibcode:2008Natur.452..713L. doi:10.1038/nature06731. PMC 2377396. PMID 18337722.
31. Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu S, Okazawa H (January 2015). "HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice". EMBO Mol Med. 7 (1): 78–101. doi:10.15252/emmm.201404392. PMC 4309669. PMID 25510912.

External links

• GeneReviews/NIH/NCBI/UW entry on Spinocerebellar Ataxia Type 1
• ataxin-1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ATXN1 genome location and ATXN1 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P54253 (Ataxin-1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.