Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation
Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation
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DOI：
10.1523/jneurosci.5673-09.2010
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发表时间：
2010-03
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通讯作者：
Zaira Ortega;M. Diaz-hernandez;Christa J. Maynard;F. Hernández;N. Dantuma;J. Lucas
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作者：
Zaira Ortega;M. Diaz-hernandez;Christa J. Maynard;F. Hernández;N. Dantuma;J. Lucas
神经退行性疾病中细胞内泛素化包涵体的存在和泛素/蛋白酶体系统（UPS）在降解异常有害蛋白中的作用引起了UPS损伤是神经退行性过程的基础的假设。然而，对于多聚谷氨酰胺疾病如亨廷顿病（HD），这仍然存在争议。尽管在细胞模型中的研究已经提供了支持归因于突变亨廷顿蛋白（N-mutHtt）的N-末端片段表达的UPS损伤的证据，但在小鼠模型中的类似研究未能做到这一点。此外，我们最近已经表明，在N-mutHtt小鼠脑中报告的多聚泛素缀合物的增加发生在没有一般UPS损伤的情况下。在本研究中，我们的目的是澄清潜在的N-mutHtt损害UPS功能在体内以及神经元可能会适应后，长期暴露于N-mutHtt的遗传模型的机制。通过将UPS报告小鼠与HD的诱导型小鼠模型相结合，我们首次证明了多聚谷氨酰胺诱导的体内整体UPS损伤。急性N-mutHtt表达后UPS受损短暂发生，恢复与包涵体（IB）的出现相关。一致地，在细胞和动物模型中，当通过施用N-mutHtt聚集抑制剂来防止IB形成时，UPS恢复不发生。最后，在组成型表达N-mutHtt的老年小鼠中没有检测到UPS损伤，尽管脑蛋白酶体活性与年龄相关。因此，我们的数据通过显示N-mutHtt确实可以在体内损害UPS功能并且N-mutHtt聚集导致UPS功能的持久恢复来调和先前的矛盾报道。
The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role of the ubiquitin/proteasome system (UPS) in degrading abnormal hazardous proteins have given rise to the hypothesis that UPS-impairment underlies neurodegenerative processes. However, this remains controversial for polyglutamine disorders such as Huntington disease (HD). Whereas studies in cellular models have provided evidence in favor of UPS-impairment attributable to expression of the N-terminal fragment of mutant huntingtin (N-mutHtt), similar studies on mouse models failed to do so. Furthermore, we have recently shown that the increase in polyubiquitin conjugates reported in the brain of N-mutHtt mice occurs in the absence of a general UPS-impairment. In the present study we aim to clarify the potential of N-mutHtt to impair UPS function in vivo as well as the mechanisms by which neurons may adapt after prolonged exposure to N-mutHtt in genetic models. By combining UPS reporter mice with an inducible mouse model of HD, we demonstrate for the first time polyglutamine-induced global UPS-impairment in vivo. UPS-impairment occurred transiently after acute N-mutHtt expression and restoration correlated with appearance of inclusion bodies (IBs). Consistently, UPS recovery did not take place when IB formation was prevented through administration of N-mutHtt aggregation-inhibitors in both cellular and animal models. Finally, no UPS-impairment was detected in old mice constitutively expressing N-mutHtt despite the age-associated decrease in brain proteasome activity. Therefore, our data reconcile previous contradictory reports by showing that N-mutHtt can indeed impair UPS function in vivo and that N-mutHtt aggregation leads to long lasting restoration of UPS function.