α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models

Alpha-synuclein (alpha Syn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alpha Syn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alpha Syn 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 alpha Syn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alpha Syn-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.