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

Christopher J. Cummings, Eyal Reinstein, Sun Yaling, Barbara Antalffy, Yong Hui Jiang, Aaron Ciechanover, Harry T. Orr, Arthur L. Beaudet, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

424 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)879-892
Number of pages14
JournalNeuron
Volume24
Issue number4
DOIs
StatePublished - Dec 1999

Bibliographical note

Funding Information:
We thank V. Brandt for her editorial help. This work is supported by grants from the National Institutes of Heath (NS27699 and NS22920) to H. Y. Z. and (HD37283) to A. L. B. and by the Baylor Mental Retardation Research Center. H. Y. Z. is a Howard Hughes Medical Institute Investigator.

Fingerprint

Dive into the research topics of 'Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice'. Together they form a unique fingerprint.

Cite this