Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice

Neuron. 2003 May 8;38(3):375-87. doi: 10.1016/s0896-6273(03)00258-7.

Abstract

Polyglutamine-induced neurodegeneration in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degradation machinery. Since phosphorylation is a prominent mechanism by which these processes are regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphorylated. Residue 776 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in tissue culture cells. The importance of S776 for polyglutamine-induced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice. These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially reduced. These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Ataxin-1
  • Ataxins
  • CHO Cells
  • COS Cells
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cricetinae
  • Disease Models, Animal
  • Female
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / genetics
  • Peptides / metabolism*
  • Phenotype
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • Serine / genetics
  • Serine / metabolism*
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism*
  • Spinocerebellar Ataxias / physiopathology
  • Trinucleotide Repeat Expansion / genetics

Substances

  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine
  • Serine