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

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