Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
J Mol Biol. 2013 Nov 15;425(22):4614-28. doi: 10.1016/j.jmb.2013.08.006. Epub 2013 Aug 13.
Aggregated α-synuclein is one of the main components of the pathological Lewy bodies associated with Parkinson's disease (PD). Many other proteins, including chaperones such as Hsp90 and Hsp70, have been found co-localized with Lewy bodies and the expression levels of Hsp90 have been found to be increased in brains of PD patients. Although the role of Hsp70 in the aggregation of α-synuclein has been extensively studied, relatively little is known about the effect of Hsp90 on this process. Here, we have investigated if Hsp90 can prevent the aggregation of the A53T pathological mutant of α-synuclein in vitro. A detailed study using many biophysical methods has revealed that Hsp90 prevents α-synuclein from aggregating in an ATP-independent manner and that it forms a strong complex with the transiently populated toxic oligomeric α-synuclein species formed along the aggregation pathway. We have also shown that, upon forming a complex with Hsp90, the oligomers are rendered harmless and nontoxic to cells. Thus, we have clear evidence that Hsp90 is likely to play an important role on these processes in vivo.
聚集的α-突触核蛋白是与帕金森病（PD）相关的病理性路易体的主要成分之一。许多其他蛋白质，包括热休克蛋白 90（Hsp90）和热休克蛋白 70（Hsp70）等伴侣蛋白，已被发现与路易体共定位，并且 PD 患者大脑中的 Hsp90 表达水平升高。尽管 Hsp70 在 α-突触核蛋白聚集中的作用已被广泛研究，但关于 Hsp90 对该过程的影响知之甚少。在这里，我们研究了 Hsp90 是否可以在体外防止 A53T 病理性突变的 α-突触核蛋白聚集。使用多种生物物理方法进行的详细研究表明，Hsp90 以非 ATP 依赖的方式阻止 α-突触核蛋白聚集，并且它与沿聚集途径形成的短暂存在的毒性寡聚体 α-突触核蛋白形成强复合物。我们还表明，与 Hsp90 形成复合物后，寡聚物对细胞无害且无毒。因此，我们有明确的证据表明 Hsp90 很可能在体内这些过程中发挥重要作用。
