Ataxin 1

ATXN1 is conserved across multiple species, including humans, mice, and Drosophila.{{cite web|url=https://www.uniprot.org/uniprot/Q9W3V7|title=Atx-1 - Ataxin 1 - Drosophila melanogaster (Fruit fly) - Atx-1 gene & protein|website=www.uniprot.org|language=en|access-date=2018-01-11}}

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.{{cite journal | vauthors = Orr HT, Chung MY, Banfi S, Kwiatkowski TJ, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY | title = Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1 | language = En | journal = Nature Genetics | volume = 4 | issue = 3 | pages = 221–6 | date = July 1993 | pmid = 8358429 | doi = 10.1038/ng0793-221 | s2cid = 8877695 }}

Notable features of the Ataxin-1 protein structure{{cite journal | vauthors = Zoghbi HY, Orr HT | title = Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1 | language = en | journal = The Journal of Biological Chemistry | volume = 284 | issue = 12 | pages = 7425–9 | date = March 2009 | pmid = 18957430 | doi = 10.1074/jbc.r800041200 | pmc = 2658037 | doi-access = free }} 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

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{{cite journal | vauthors = Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY | title = ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology | journal = Cell | volume = 127 | issue = 7 | pages = 1335–47 | date = December 2006 | pmid = 17190598 | doi = 10.1016/j.cell.2006.11.038 | s2cid = 14900395 | doi-access = free }} and parts of the RNA splicing machinery.{{cite journal | vauthors = Kim E, Lee Y, Choi S, Song JJ | title = Structural basis of the phosphorylation dependent complex formation of neurodegenerative disease protein Ataxin-1 and RBM17 | journal = Biochemical and Biophysical Research Communications | volume = 449 | issue = 4 | pages = 399–404 | date = July 2014 | pmid = 24858692 | doi = 10.1016/j.bbrc.2014.05.063 }}

Ataxin 1 has been shown to interact with:

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• C2orf27,{{cite journal | vauthors = 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 | title = Development and application of a DNA microarray-based yeast two-hybrid system | journal = Nucleic Acids Research | volume = 41 | issue = 3 | pages = 1496–507 | year = 2013 | pmid = 23275563 | pmc = 3561971 | doi = 10.1093/nar/gks1329 }}
• Coilin,{{cite journal | vauthors = Hong S, Ka S, Kim S, Park Y, Kang S | title = p80 coilin, a coiled body-specific protein, interacts with ataxin-1, the SCA1 gene product | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1638 | issue = 1 | pages = 35–42 | date = May 2003 | pmid = 12757932 | doi = 10.1016/s0925-4439(03)00038-3 | doi-access = free }}{{cite journal | vauthors = Hong S, Lee S, Cho SG, Kang S | title = UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1 | journal = Biochemical and Biophysical Research Communications | volume = 371 | issue = 2 | pages = 256–60 | date = June 2008 | pmid = 18439907 | doi = 10.1016/j.bbrc.2008.04.066 }}
• Glyceraldehyde 3-phosphate dehydrogenase,{{cite journal | vauthors = Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY | title = Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase | journal = Human Molecular Genetics | volume = 5 | issue = 9 | pages = 1311–8 | date = September 1996 | pmid = 8872471 | doi = 10.1093/hmg/5.9.1311 | doi-access = free }}
• CIC{{cite journal | vauthors = Lee Y | title = Regulation and function of capicua in mammals | journal = Experimental & Molecular Medicine | volume = 52 | issue = 4 | pages = 531–537 | date = April 2020 | pmid = 32238859 | pmc = 7210929 | doi = 10.1038/s12276-020-0411-3 | url = }}{{cite journal | vauthors = 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 | title = Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans | journal = Nature Genetics | volume = 49 | issue = 4 | pages = 527–536 | date = April 2017 | pmid = 28288114 | pmc = 5374026 | doi = 10.1038/ng.3808 | url = }}
• UBE2E1, and
• USP7.{{cite journal | vauthors = Hong S, Kim SJ, Ka S, Choi I, Kang S | title = USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product | journal = Molecular and Cellular Neurosciences | volume = 20 | issue = 2 | pages = 298–306 | date = June 2002 | pmid = 12093161 | doi = 10.1006/mcne.2002.1103 | s2cid = 41295664 }}

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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. 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.{{cite journal | vauthors = Matilla T, Volpini V, Genís D, Rosell J, Corral J, Dávalos A, Molins A, Estivill X | title = 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 | journal = Human Molecular Genetics | volume = 2 | issue = 12 | pages = 2123–8 | date = December 1993 | pmid = 8111382 | doi=10.1093/hmg/2.12.2123}} Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression.{{cite book|doi=10.1016/B978-0-444-51892-7.00025-5|title=Handbook of Clinical Neurology|last1=Donato|first1=Stefano Di|last2=Mariotti|first2=Caterina|last3=Taroni|first3=Franco |chapter=Spinocerebellar ataxia type 1|date=2012-01-01|publisher=Elsevier|editor-last=Dürr|editor-first=Sankara H. Subramony and Alexandra|series=Ataxic Disorders|volume=103|pages=399–421|pmid=21827903|isbn=9780444518927|s2cid=68966133 }}

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

Mutant Ataxin-1 protein spontaneously misfolds and forms aggregates in cells,{{cite journal | vauthors = Shastry BS | title = Neurodegenerative disorders of protein aggregation | journal = Neurochemistry International | volume = 43 | issue = 1 | pages = 1–7 | date = July 2003 | pmid = 12605877 | doi = 10.1016/s0197-0186(02)00196-1 | s2cid = 31191916 }} 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.{{cite journal | vauthors = Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT | title = Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice | journal = Cell | volume = 95 | issue = 1 | pages = 41–53 | year = 1998 | pmid = 9778246 | doi = 10.1016/s0092-8674(00)81781-x | s2cid = 638016 | doi-access = free }} Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.{{cite journal | vauthors = Petrakis S, Raskó T, Russ J, Friedrich RP, Stroedicke M, Riechers SP, Muehlenberg K, Möller A, Reinhardt A, Vinayagam A, Schaefer MH, Boutros M, Tricoire H, Andrade-Navarro MA, Wanker EE | display-authors = 6 | title = Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1 | journal = PLOS Genetics | volume = 8 | issue = 8 | pages = e1002897 | date = Aug 2012 | pmid = 22916034 | pmc = 3420947 | doi = 10.1371/journal.pgen.1002897 | doi-access = free }}

{{cite journal | vauthors = 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 | title = CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation | journal = The Journal of Biological Chemistry | volume = 281 | issue = 36 | pages = 26714–24 | date = September 2006 | pmid = 16831871 | doi = 10.1074/jbc.M601603200 | doi-access = free }}

{{cite journal | vauthors = de Chiara C, Menon RP, Dal Piaz F, Calder L, Pastore A | title = Polyglutamine is not all: the functional role of the AXH domain in the ataxin-1 protein | journal = Journal of Molecular Biology | volume = 354 | issue = 4 | pages = 883–93 | date = December 2005 | pmid = 16277991 | doi = 10.1016/j.jmb.2005.09.083 }}

{{cite journal | vauthors = Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY | title = The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins | journal = Cell | volume = 122 | issue = 4 | pages = 633–44 | date = August 2005 | pmid = 16122429 | doi = 10.1016/j.cell.2005.06.012 | s2cid = 16706329 | doi-access = free }}

{{cite journal | vauthors = Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, Tsai CC | title = Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1 | journal = The EMBO Journal | volume = 24 | issue = 18 | pages = 3339–51 | date = September 2005 | pmid = 16121196 | pmc = 1224676 | doi = 10.1038/sj.emboj.7600785 }}

{{cite journal | vauthors = Park Y, Hong S, Kim SJ, Kang S | title = Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product | journal = Molecules and Cells | volume = 19 | issue = 1 | pages = 23–30 | date = February 2005 | doi = 10.1016/S1016-8478(23)13132-3 | pmid = 15750336 | doi-access = free }}

{{cite journal | vauthors = Irwin S, Vandelft M, Pinchev D, Howell JL, Graczyk J, Orr HT, Truant R | title = RNA association and nucleocytoplasmic shuttling by ataxin-1 | journal = Journal of Cell Science | volume = 118 | issue = Pt 1 | pages = 233–42 | date = January 2005 | pmid = 15615787 | doi = 10.1242/jcs.01611 | s2cid = 14401082 | doi-access = }}

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).{{cite journal | vauthors = Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY | title = Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1 | language = en | journal = Nature | volume = 452 | issue = 7188 | pages = 713–8 | date = April 2008 | pmid = 18337722 | pmc = 2377396 | doi = 10.1038/nature06731 | bibcode = 2008Natur.452..713L }} This, in turn, could alter the expression of the genes ataxin-1 regulates, leading to disease.

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.{{cite journal |vauthors=Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu S, Okazawa H |title=HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice |journal=EMBO Mol Med |volume=7 |issue=1 |pages=78–101 |date=January 2015 |pmid=25510912 |pmc=4309669 |doi=10.15252/emmm.201404392 }} 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.

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{{Reflist|32em}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sca1 GeneReviews/NIH/NCBI/UW entry on Spinocerebellar Ataxia Type 1]
• {{MeshName|ataxin-1}}
• {{UCSC gene info|ATXN1}}
• {{PDBe-KB2|P54253|Ataxin-1}}

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Category:Proteins