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

• DOI: 10.1126/science.1129462
• Publication Date: 2006-06-23T00:52:44Z
• Authors: Antony A. Cooper; Aaron D. Gitler; Anil Cashikar; Cole M. Haynes; Kathryn J. Hill; Bhupinder Bhullar; Kangning Liu; Kexiang Xu; Katherine E. Stra...; Fang Liu; Songsong Cao; Kim A. Caldwell; Guy A. Caldwell; Gerald Marsischky; Richard D. Kolodner; Joshua LaBaer; Jean-Christophe R...; Nancy M. Bonini; Susan Lindquist
• Keywords: Rab; LRRK2; Calnexin; Inclusion bodies; COPI

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