Hsp90 Inhibits α-Synuclein Aggregation by Interacting with Soluble Oligomers
Hsp90 Inhibits α-Synuclein Aggregation by Interacting with Soluble Oligomers
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DOI：
10.1016/j.jmb.2013.08.006
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发表时间：
2013-11-15
影响因子：
5.6
通讯作者：
Jackson, Sophie E.
中科院分区：
文献类型：
--
作者：
Daturpalli, Soumya;Waudby, Christopher A.;Jackson, Sophie E.
聚集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，包括伴侣蛋白，如Hsp90和Hsp70，已被发现与路易小体共定位，并且在PD患者的大脑中发现Hsp90的表达水平升高。尽管Hsp70在α -突触核蛋白聚集中的作用已被广泛研究，但对Hsp90在这一过程中的作用知之甚少。在这里，我们研究了Hsp90是否可以在体外阻止α -突触核蛋白A53T病理突变体的聚集。一项使用多种生物物理方法的详细研究表明，Hsp90阻止α -突触核蛋白以不依赖于atp的方式聚集，并与沿聚集途径形成的瞬时聚集的有毒寡聚α -突触核蛋白形成强复合物。我们还表明，在与Hsp90形成复合物后，低聚物对细胞是无害和无毒的。因此，我们有明确的证据表明，Hsp90可能在体内这些过程中发挥重要作用。爱思唯尔有限公司版权所有版权所有。
Aggregated alpha a-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 alpha-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 alpha-synuclein in vitro. A detailed study using many biophysical methods has revealed that Hsp90 prevents alpha-synuclein from aggregating in an ATP-independent manner and that it forms a strong complex with the transiently populated toxic oligomeric alpha-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. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.