α-Synuclein: Membrane Interactions and Toxicity in Parkinson's Disease

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