TY - JOUR
T1 - Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice
AU - Cummings, Christopher J.
AU - Reinstein, Eyal
AU - Yaling, Sun
AU - Antalffy, Barbara
AU - Jiang, Yong Hui
AU - Ciechanover, Aaron
AU - Orr, Harry T.
AU - Beaudet, Arthur L.
AU - Zoghbi, Huda Y.
N1 - 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.
PY - 1999/12
Y1 - 1999/12
N2 - 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.
AB - 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.
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U2 - 10.1016/S0896-6273(00)81035-1
DO - 10.1016/S0896-6273(00)81035-1
M3 - Article
C2 - 10624951
AN - SCOPUS:0033391428
SN - 0896-6273
VL - 24
SP - 879
EP - 892
JO - Neuron
JF - Neuron
IS - 4
ER -