Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signaled to DNA damage by ataxia-telangiectasia mutated kinase

Hum Mol Genet. 2021 May 17;30(8):706-715. doi: 10.1093/hmg/ddab074.


Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington's Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia-telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Ataxin-1 / genetics*
  • Ataxin-1 / metabolism
  • Cell Line
  • DNA Damage*
  • Disease Models, Animal
  • Drosophila / genetics
  • Drosophila / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Humans
  • Microscopy, Confocal
  • Mutation
  • Peptides / genetics
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / pathology
  • Trinucleotide Repeats / genetics


  • Ataxin-1
  • Peptides
  • polyglutamine
  • Ataxia Telangiectasia Mutated Proteins

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