α-Synuclein impairs macroautophagy: implications for Parkinson’s disease

2010/09/20 by Ashley R. Winslow, Chien-Wen Chen, Chien‐Wen Chen +13 · 33 citations
Medicine · #Autophagy in Disease and Therapy #Parkinson's Disease Mechanisms and Treatments #Lysosomal Storage Disorders Research

paper · pdf · doi:10.1083/jcb.201003122

Abstract

Parkinson's disease (PD) is characterized pathologically by intraneuronal inclusions called Lewy bodies, largely comprised of α-synuclein. Multiplication of the α-synuclein gene locus increases α-synuclein expression and causes PD. Thus, overexpression of wild-type α-synuclein is toxic. In this study, we demonstrate that α-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Our data show that α-synuclein compromises autophagy via Rab1a inhibition and Rab1a overexpression rescues the autophagy defect caused by α-synuclein. Inhibition of autophagy by α-synuclein overexpression or Rab1a knockdown causes mislocalization of the autophagy protein, Atg9, and decreases omegasome formation. Rab1a, α-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors.

Citations

• Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein
• Dopamine-modified α-synuclein blocks chaperone-mediated autophagy

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