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

被引:413
作者
Cummings, CJ
Reinstein, E
Sun, YL
Antalffy, B
Jiang, YH
Ciechanover, A
Orr, HT
Beaudet, AL
Zoghbi, HY [1 ]
机构
[1] Baylor Coll Med, Cell & Mol Biol Program, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[5] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
[6] Technion Israel Inst Technol, Dept Biochem, IL-31096 Haifa, Israel
[7] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA
[8] Univ Minnesota, Dept Pathol, Minneapolis, MN 55455 USA
[9] Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA
关键词
D O I
10.1016/S0896-6273(00)81035-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 Nls. Nonetheless, the Purkinje cell pathology is markedly worse than that of SCA1 mice. Taken together, Nts are not necessary to induce neurodegeneration, but impaired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 pathogenesis.
引用
收藏
页码:879 / 892
页数:14
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