α-Synuclein protein advances Parkinson’s by preventing neurons from clearing debris

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

JCB Home > 2010 Archive > 20 September > Winslow et al. 190 (6): 1023

Ashley R. Winslow1, Chien-Wen Chen1,3, Silvia Corrochano4, Abraham Acevedo-Arozena4, David E. Gordon2, Andrew A. Peden2, Maike Lichtenberg1, Fiona M. Menzies1, Brinda Ravikumar1, Sara Imarisio1,3, Steve Brown4, Cahir J. O’Kane3, and David C. Rubinsztein1

1Department of Medical Genetics and 2Department of Clinical Biochemistry, Cambridge Institute for Medical Research and 3Department of Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK
4Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 0RD, England, UK

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.

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