The Aggregation and Fibrillation of -Synuclein

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• 作者：Anthony L. Fink
• 刊名：Accounts of Chemical Research
• 出版年：2006
• 出版时间：September 2006
• 年：2006
• 卷：39
• 期：9
• 页码：628 - 634
• 全文大小：357K
• 年卷期：v.39,no.9(September 2006)
• ISSN：1520-4898

文摘

lpha.gif" BORDER=0>-Synuclein is a small (14 kDa), abundant, intrinsically disorderedpresynaptic protein, whose aggregation is believed to be a criticalstep in Parkinson's disease (PD). The kinetics of lpha.gif" BORDER=0>-synucleinfibrillation are consistent with a nucleation-dependent mechanism,in which the critical early stage of the structural transformationinvolves a partially folded intermediate. Although the basis for thetoxic effects of aggregated lpha.gif" BORDER=0>-synuclein are unknown, it has beenproposed that transient oligomers are responsible, possibly byforming pores in membranes. In this Account, I discuss ourinvestigations into the molecular basis for lpha.gif" BORDER=0>-synuclein aggregation/fibrillation, including factors that either accelerate or inhibitfibrillation, effects of molecular crowding, oxidation, point mutations, and lipid membranes, as well as the variety of conformationaland oligomeric states that lpha.gif" BORDER=0>-synuclein can adopt. It is apparentthat neuronal cells must have a very fine balance of factors thatcontrol the levels and potential aggregation of lpha.gif" BORDER=0>-synuclein.