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

TLDR

Parkinson’s disease is marked by Lewy bodies rich in α‑synuclein, and gene multiplication that increases its expression is known to be toxic. The study investigates whether α‑synuclein overexpression disrupts macroautophagy in cells and mice. α‑synuclein impairs macroautophagy by inhibiting Rab1a, leading to Atg9 mislocalization and reduced omegasome formation, while Rab1a overexpression restores autophagic function.

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.