α-synuclein: Membrane interactions and toxicity in parkinson's disease

Pavan K. Auluck, Gabriela Caraveo, Susan Lindquist

Research output: Contribution to journalReview articlepeer-review

353 Scopus citations

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 othermodel 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 withmembranes and regulation of synaptic vesicles as well as howoverexpression ofα-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.

Original languageEnglish (US)
Pages (from-to)211-233
Number of pages23
JournalAnnual Review of Cell and Developmental Biology
Volume26
DOIs
StatePublished - Nov 10 2010

Keywords

  • neurodegeneration
  • protein folding
  • vesicle trafficking

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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