Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. or15


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

Antony A. Cooper, Aaron D. Gitler, Anil Cashikar, Cole M. Haynes, Kathryn J. Hill, Bhupinder Bhullar, Kangning Liu, Kexiang Xu, Katherine E. Strathearn, Fang Liu, Songsong Cao, Kim A. Caldwell, Guy A. Caldwell, Gerald Marsischky, Richard D. Kolodner, Joshua LaBaer, Jean-Christophe Rochet, Nancy M. Bonini, and Susan Lindquist

Abstract: Science 22 June 2006 (10.1126/science.1129462) (Science Express Report)

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 genome-wide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab GTPase 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.


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