Arrasate Montserrat, Mitra Siddhartha, Schweitzer Erik S, Segal Mark R, Finkbeiner Steven
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141, USA.
Nature. 2004 Oct 14;431(7010):805-10. doi: 10.1038/nature02998.
Huntington's disease is caused by an abnormal polyglutamine expansion within the protein huntingtin and is characterized by microscopic inclusion bodies of aggregated huntingtin and by the death of selected types of neuron. Whether inclusion bodies are pathogenic, incidental or a beneficial coping response is controversial. To resolve this issue we have developed an automated microscope that returns to precisely the same neuron after arbitrary intervals, even after cells have been removed from the microscope stage. Here we show, by survival analysis, that neurons die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body. Rather, the amount of diffuse intracellular huntingtin predicts whether and when inclusion body formation or death will occur. Surprisingly, inclusion body formation predicts improved survival and leads to decreased levels of mutant huntingtin elsewhere in a neuron. Thus, inclusion body formation can function as a coping response to toxic mutant huntingtin.
亨廷顿舞蹈症是由亨廷顿蛋白内异常的多聚谷氨酰胺扩增引起的，其特征是聚集的亨廷顿蛋白形成的微观包涵体以及特定类型神经元的死亡。包涵体是致病的、偶然出现的还是一种有益的应对反应，这存在争议。为了解决这个问题，我们开发了一种自动显微镜，即使细胞已从显微镜载物台上移除，它也能在任意时间间隔后精确返回同一个神经元。在此我们通过生存分析表明，神经元以与时间无关的方式死亡，但这种方式取决于突变型亨廷顿蛋白的剂量和多聚谷氨酰胺扩增；许多神经元在不形成包涵体的情况下死亡。相反，细胞内弥漫性亨廷顿蛋白的量可预测包涵体形成或死亡是否会发生以及何时发生。令人惊讶的是，包涵体形成预示着存活率提高，并导致神经元其他部位突变型亨廷顿蛋白水平降低。因此，包涵体形成可作为对有毒突变型亨廷顿蛋白的一种应对反应。
