Biology:Ataxin 1

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Short description: Protein-coding gene in the species Homo sapiens

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.[1][2]

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.[3]

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.[4]

Structure

Notable features of the Ataxin-1 protein structure[5] include:

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[6] and parts of the RNA splicing machinery.[7]

Interactions

Ataxin 1 has been shown to interact with:


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.[4] 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.[15][4] Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression.[16]

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,[17] 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.[18] Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.[19]

[20] [21] [22] [23] [24] [25]

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).[26] 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.[27] 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.[27]

References

  1. ↑ "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. Jun 1992. doi:10.1159/000133291. PMID 1582256. 
  2. ↑ "Entrez Gene: ATXN1 ataxin 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6310. 
  3. ↑ "Atx-1 - Ataxin 1 - Drosophila melanogaster (Fruit fly) - Atx-1 gene & protein" (in en). https://www.uniprot.org/uniprot/Q9W3V7. 
  4. ↑ 4.0 4.1 4.2 "Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1" (in En). Nature Genetics 4 (3): 221–6. July 1993. doi:10.1038/ng0793-221. PMID 8358429. 
  5. ↑ "Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1" (in en). The Journal of Biological Chemistry 284 (12): 7425–9. March 2009. doi:10.1074/jbc.r800041200. PMID 18957430. 
  6. ↑ "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology". Cell 127 (7): 1335–47. December 2006. doi:10.1016/j.cell.2006.11.038. PMID 17190598. 
  7. ↑ "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. July 2014. doi:10.1016/j.bbrc.2014.05.063. PMID 24858692. 
  8. ↑ "Development and application of a DNA microarray-based yeast two-hybrid system". Nucleic Acids Research 41 (3): 1496–507. 2013. doi:10.1093/nar/gks1329. PMID 23275563. 
  9. ↑ "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. May 2003. doi:10.1016/s0925-4439(03)00038-3. PMID 12757932. 
  10. ↑ 10.0 10.1 "UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1". Biochemical and Biophysical Research Communications 371 (2): 256–60. June 2008. doi:10.1016/j.bbrc.2008.04.066. PMID 18439907. 
  11. ↑ "Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase". Human Molecular Genetics 5 (9): 1311–8. September 1996. doi:10.1093/hmg/5.9.1311. PMID 8872471. 
  12. ↑ "Regulation and function of capicua in mammals". Experimental & Molecular Medicine 52 (4): 531–537. April 2020. doi:10.1038/s12276-020-0411-3. PMID 32238859. 
  13. ↑ "Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans". Nature Genetics 49 (4): 527–536. April 2017. doi:10.1038/ng.3808. PMID 28288114. 
  14. ↑ "USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product". Molecular and Cellular Neurosciences 20 (2): 298–306. June 2002. doi:10.1006/mcne.2002.1103. PMID 12093161. 
  15. ↑ "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. December 1993. doi:10.1093/hmg/2.12.2123. PMID 8111382. 
  16. ↑ Donato, Stefano Di; Mariotti, Caterina; Taroni, Franco (2012-01-01). "Spinocerebellar ataxia type 1". in Dürr, Sankara H. Subramony and Alexandra. Handbook of Clinical Neurology. Ataxic Disorders. 103. Elsevier. pp. 399–421. doi:10.1016/B978-0-444-51892-7.00025-5. ISBN 9780444518927. 
  17. ↑ "Neurodegenerative disorders of protein aggregation". Neurochemistry International 43 (1): 1–7. July 2003. doi:10.1016/s0197-0186(02)00196-1. PMID 12605877. 
  18. ↑ "Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice". Cell 95 (1): 41–53. 1998. doi:10.1016/s0092-8674(00)81781-x. PMID 9778246. 
  19. ↑ "Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1". PLOS Genetics 8 (8): e1002897. Aug 2012. doi:10.1371/journal.pgen.1002897. PMID 22916034. 
  20. ↑ "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. September 2006. doi:10.1074/jbc.M601603200. PMID 16831871. 
  21. ↑ "Polyglutamine is not all: the functional role of the AXH domain in the ataxin-1 protein". Journal of Molecular Biology 354 (4): 883–93. December 2005. doi:10.1016/j.jmb.2005.09.083. PMID 16277991. 
  22. ↑ "The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins". Cell 122 (4): 633–44. August 2005. doi:10.1016/j.cell.2005.06.012. PMID 16122429. 
  23. ↑ "Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1". The EMBO Journal 24 (18): 3339–51. September 2005. doi:10.1038/sj.emboj.7600785. PMID 16121196. 
  24. ↑ "Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product". Molecules and Cells 19 (1): 23–30. February 2005. doi:10.1016/S1016-8478(23)13132-3. PMID 15750336. 
  25. ↑ "RNA association and nucleocytoplasmic shuttling by ataxin-1". Journal of Cell Science 118 (Pt 1): 233–42. January 2005. doi:10.1242/jcs.01611. PMID 15615787. 
  26. ↑ "Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1" (in en). Nature 452 (7188): 713–8. April 2008. doi:10.1038/nature06731. PMID 18337722. Bibcode: 2008Natur.452..713L. 
  27. ↑ 27.0 27.1 "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. January 2015. doi:10.15252/emmm.201404392. PMID 25510912. 

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



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