Ataxin 1

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

ATXN1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesATXN1, ATX1, D6S504E, SCA1, ataxin 1
External IDsOMIM: 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 MbChr 13: 45.7 – 46.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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:

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]

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.
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