α-Synuclein: membrane interactions and toxicity in Parkinson's disease.
In the late 1990s, mutations in the synaptic protein &#x03B1;-synuclein (&#x03B1;-syn) were identified in families with hereditary Parkinson's disease (PD). Rapidly, &#x03B1;-syn became the target of numerous investigations that have transformed our understanding of the pathogenesis underlying this disorder. &#x03B1;-Syn is the major component of Lewy bodies (LBs), cytoplasmic protein aggregates that form in the neurons of PD patients. &#x03B1;-Syn interacts with lipid membranes and adopts amyloid conformations that deposit within LBs. Work in yeast and other model systems has revealed that &#x03B1;-syn-associated toxicity might be the consequence of abnormal membrane interactions and alterations in vesicle trafficking. Here we review evidence regarding &#x03B1;-syn's normal interactions with membranes and regulation of synaptic vesicles as well as how overexpression of &#x03B1;-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.
Auluck
Pavan K
PK
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. auluck@wi.mit.edu
Caraveo
Gabriela
G
Lindquist
Susan
S
D000818:Animals; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D022161:Transport Vesicles / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein