Winslow, A.R., Chen, C.W., Corrochano, S., Acevedo-Arozena, A., Gordon, D.E., Peden, A.A., Lichtenberg, M., Menzies, F.M., Ravikumar, B., Imarisio, S., Brown, S., O'Kane, C.J., Rubinsztein, D.C. (2010). α-Synuclein impairs macroautophagy: implications for Parkinson's disease.  J. Cell Biol. 190(6): 1023--1037.

FBrf0214188

Research paper

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.

PMC3101586 (PMC) (EuropePMC)