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Published Online June 22, 2006
Science DOI: 10.1126/science.1129462

Research Articles

Submitted on May 2, 2006
Accepted on June 12, 2006

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

Antony A. Cooper 1, Aaron D. Gitler 2, Anil Cashikar 3, Cole M. Haynes 4, Kathryn J. Hill 5, Bhupinder Bhullar 6, Kangning Liu 7, Kexiang Xu 8, Katherine E. Strathearn 9, Fang Liu 9, Songsong Cao 10, Kim A. Caldwell 10, Guy A. Caldwell 10, Gerald Marsischky 11, Richard D. Kolodner 12, Joshua LaBaer 11, Jean-Christophe Rochet 9, Nancy M. Bonini 7, Susan Lindquist 13*

1 School of Biological Sciences,, University of Missouri-Kansas City, Kansas City, MO, USA; Present address: Garvan Institute of Medical Research, Sydney, Australia.
2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Present address: Medical College of Georgia, Augusta, GA, USA.
4 School of Biological Sciences,University of Missouri-Kansas City, Kansas City, MO, USA; Present address: New York University, New York, NY, USA.
5 School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO, USA; Present address: Garvan Institute of Medical Research, Sydney, Australia.
6 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Harvard Institute of Proteomics, 320 Charles St, Cambridge, MA 02141, USA.
7 Department of Biology, University of Pennsylvania, USA; Howard Hughes Medical Institute, Philadelphia, PA 19104, USA.
8 Department of Biology, University of Pennsylvania, USA.
9 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-2091, USA.
10 Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
11 Harvard Institute of Proteomics, 320 Charles St, Cambridge, MA 02141, USA.
12 Ludwig Institute for Cancer Research, UC San Diego School of Medicine, La Jolla, CA, USA.
13 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed.
Susan Lindquist , E-mail: lindquist_admin{at}wi.mit.edu

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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