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Annu Rev Cell Dev Biol. 2010;26:211-33. doi: 10.1146/annurev.cellbio.042308.113313.

α-Synuclein: membrane interactions and toxicity in Parkinson's disease.

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  • 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. auluck@wi.mit.edu

Abstract

In the late 1990s, mutations in the synaptic protein α-synuclein (α-syn) were identified in families with hereditary Parkinson's disease (PD). Rapidly, α-syn became the target of numerous investigations that have transformed our understanding of the pathogenesis underlying this disorder. α-Syn is the major component of Lewy bodies (LBs), cytoplasmic protein aggregates that form in the neurons of PD patients. α-Syn interacts with lipid membranes and adopts amyloid conformations that deposit within LBs. Work in yeast and other model systems has revealed that α-syn-associated toxicity might be the consequence of abnormal membrane interactions and alterations in vesicle trafficking. Here we review evidence regarding α-syn's normal interactions with membranes and regulation of synaptic vesicles as well as how overexpression of α-syn yields global cellular dysfunction. Finally, we present a model linking vesicle dynamics to toxicity with the sincere hope that understanding these disease mechanisms will lead to the development of novel, potent therapeutics.

PMID:
20500090
[PubMed - indexed for MEDLINE]
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