-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models
Antony A. Cooper,1*
Aaron D. Gitler,2*
Anil Cashikar,2
Cole M. Haynes,1
Kathryn J. Hill,1
Bhupinder Bhullar,2,3
Kangning Liu,4,5
Kexiang Xu,4
Katherine E. Strathearn,6
Fang Liu,6
Songsong Cao,7
Kim A. Caldwell,7
Guy A. Caldwell,7
Gerald Marsischky,3
Richard D. Kolodner,8
Joshua LaBaer,3
Jean-Christophe Rochet,6
Nancy M. Bonini,4,5
Susan Lindquist2,9||
Alpha-synuclein (
Syn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons Syn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following 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 Syn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against 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.
1 School of Biological Sciences, University of Missouri–Kansas City, Kansas City, MO 64110, USA.
2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3 Harvard Institute of Proteomics, 320 Charles Street, Cambridge, MA 02141, USA.
4 Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5 Howard Hughes Medical Institute, Philadelphia, PA 19104, USA.
6 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907–2091, USA.
7 Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA.
8 Ludwig Institute for Cancer Research, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
9 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
* These authors contributed equally to this work.
Present address: Garvan Institute of Medical Research, Sydney, Australia.
Present address: Medical College of Georgia, Augusta, GA, USA.
Present address: New York University, New York, NY, USA.
|| To whom correspondence should be addressed. E-mail: lindquist_admin{at}wi.mit.edu
