α-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models

TLDR

Alpha‑synuclein misfolding is linked to Parkinson’s disease and other neurodegenerative disorders, and its cytotoxic accumulation in yeast and neurons suggests that disruptions in basic cellular functions may underlie synucleinopathies, though its normal role remains poorly understood. In yeast, alpha‑synuclein expression first blocks ER‑to‑Golgi trafficking, and a genome‑wide screen identified trafficking proteins such as Rab1 as modifiers; overexpressing Rab1 protects dopaminergic neurons from alpha‑synuclein toxicity in Parkinson’s disease models.

Abstract

Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.