Ataxin 1

Last updated
ATXN1
Protein ATXN1 PDB 1oa8.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ATXN1 , ATX1, D6S504E, SCA1, ataxin 1
External IDs OMIM: 601556 MGI: 104783 HomoloGene: 281 GeneCards: ATXN1
Orthologs
SpeciesHumanMouse
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

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

Contents

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:

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:

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]

Related Research Articles

Repeated sequences are short or long patterns of nucleic acids that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genomic DNA is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.

<span class="mw-page-title-main">Spinocerebellar ataxia</span> Medical condition

Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

Trinucleotide repeat disorders, a subset of microsatellite expansion diseases, are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

Ataxin 7 (ATXN7) is a protein of the SCA7 gene, which contains 892 amino acids with an expandable poly(Q) region close to the N-terminus. The expandable poly(Q) motif region in the protein contributes crucially to spinocerebellar ataxia (SCA) pathogenesis by the induction of intranuclear inclusion bodies. ATXN7 is associated with both olivopontocerebellar atrophy type 3 (OPCA3) and spinocerebellar ataxia type 7 (SCA7).

Ataxin is a type of nuclear protein. The class is called ataxin because mutated forms of these proteins and their corresponding genes were found to cause progressive ataxia.

<span class="mw-page-title-main">Spinocerebellar ataxia type 6</span> Medical condition

Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.

<span class="mw-page-title-main">HMGB1</span> Mammalian protein found in Homo sapiens

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.

<span class="mw-page-title-main">Ataxin-2</span> Mammalian protein found in Homo sapiens

Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene. Mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2).

Ca<sub>v</sub>2.1 Protein-coding gene in the species Homo sapiens

Cav2.1, also called the P/Q voltage-dependent calcium channel, is a calcium channel found mainly in the brain. Specifically, it is found on the presynaptic terminals of neurons in the brain and cerebellum. Cav2.1 plays an important role in controlling the release of neurotransmitters between neurons. It is composed of multiple subunits, including alpha-1, beta, alpha-2/delta, and gamma subunits. The alpha-1 subunit is the pore-forming subunit, meaning that the calcium ions flow through it. Different kinds of calcium channels have different isoforms (versions) of the alpha-1 subunit. Cav2.1 has the alpha-1A subunit, which is encoded by the CACNA1A gene. Mutations in CACNA1A have been associated with various neurologic disorders, including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6.

<span class="mw-page-title-main">Ataxin 3</span> Protein-coding gene in the species Homo sapiens

Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.

<span class="mw-page-title-main">JPH3</span> Protein-coding gene in the species Homo sapiens

Junctophilin-3 is a protein in humans that is encoded by the JPH3 gene. The gene is approximately 97 kilobases long and is located at position 16q24.2. Junctophilin proteins are associated with the formation of junctional membrane complexes, linking the plasma membrane with the endoplasmic reticulum in excitable cells. Junctophilin-3 is specific to the brain and has an active role in neurons involved in motor coordination and memory.

Ataxin 8 opposite strand, also known as ATXN8OS, is a human gene.

<span class="mw-page-title-main">RBFOX1</span> Protein-coding gene in the species Homo sapiens

Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.

<span class="mw-page-title-main">Dentatorubral–pallidoluysian atrophy</span> Congenital disorder of nervous system

Dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a polyglutamine tract in the atrophin-1 protein. It is also known as Haw River Syndrome and Naito–Oyanagi disease. Although this condition was perhaps first described by Smith et al. in 1958, and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan.

<span class="mw-page-title-main">Capicua (protein)</span> Protein found in humans

Capicua transcriptional repressor is a protein that in humans is encoded by the CIC gene. Capicua functions as a transcriptional repressor in a way that ensures its impact on the progression of cancer, and plays a significant role in the operation of the central nervous system through its interaction with ataxin 1. The name of the protein derives from the Catalan expression cap-i-cua which literally translates to "head-and-tail".

A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units.

<span class="mw-page-title-main">Huda Zoghbi</span> Lebanese scientist

Huda Yahya Zoghbi, born Huda El-Hibri, is a Lebanese-born American geneticist, and a professor at the Departments of Molecular and Human Genetics, Neuroscience and Neurology at the Baylor College of Medicine. She is the director of the Jan and Dan Duncan Neurological Research Institute. She became the editor of the Annual Review of Neuroscience as of 2018.

<span class="mw-page-title-main">Autosomal dominant cerebellar ataxia</span> Medical condition

Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.

<span class="mw-page-title-main">Ubiquilin 4</span> Protein-coding gene in the species Homo sapiens

Ubiquilin 4 is a protein in humans that is encoded by the UBQLN4 gene. Ubiquilin 4 regulates proteasomal protein degradation.

<span class="mw-page-title-main">Spinocerebellar ataxia type 1</span> Rare neurodegenerative disorder

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cerebellar dysfunction is progressive and permanent. First onset of symptoms is normally between 30 and 40 years of age, though juvenile onset can occur. Death typically occurs within 10 to 30 years from onset.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124788 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 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. 1 2 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. 1 2 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.

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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.