Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice.


Journal Article

Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusions (NI) that alter proteasome distribution in affected SCA1 patient neurons. Here, we observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway. While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated equally well in vitro, the mutant form is three times more resistant to degradation. Inhibiting proteasomal degradation promotes ataxin-1 aggregation in transfected cells. And in mice, Purkinje cells that express mutant ataxin-1 but not a ubiquitin-protein ligase have significantly fewer NIs. Nonetheless, the Purkinje cell pathology is markedly worse than that of SCA1 mice. Taken together, NIs are not necessary to induce neurodegeneration, but impaired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 pathogenesis.

Full Text

Cited Authors

  • Cummings, CJ; Reinstein, E; Sun, Y; Antalffy, B; Jiang, Y; Ciechanover, A; Orr, HT; Beaudet, AL; Zoghbi, HY

Published Date

  • December 1999

Published In

Volume / Issue

  • 24 / 4

Start / End Page

  • 879 - 892

PubMed ID

  • 10624951

Pubmed Central ID

  • 10624951

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

International Standard Serial Number (ISSN)

  • 0896-6273

Digital Object Identifier (DOI)

  • 10.1016/s0896-6273(00)81035-1


  • eng