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Science 5 December 2003:
Vol. 302. no. 5651, pp. 1772 - 1775
DOI: 10.1126/science.1090439
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Reports

Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology

Tiago Fleming Outeiro and Susan Lindquist*

Alpha-synuclein is implicated in several neurodegenerative disorders, such as Parkinson's disease and multiple system atrophy, yet its functions remain obscure. When expressed in yeast, alpha-synuclein associated with the plasma membrane in a highly selective manner, before forming cytoplasmic inclusions through a concentration-dependent, nucleated process. Alpha-synuclein inhibited phospholipase D, induced lipid droplet accumulation, and affected vesicle trafficking. This readily manipulable system provides an opportunity to dissect the molecular pathways underlying normal alpha-synuclein biology and the pathogenic consequences of its misfolding.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.



Note added in proof: Very recently Singleton et al. (32) reported that a triplication of the {alpha}Syn locus on one chromosome (presumably doubling the expression of wild-type {alpha}Syn) causes premature onset of PD, strongly supporting our model that a small change in the expression of {alpha}Syn relative to the cell's quality-control systems causes disease-related toxicity.

* To whom correspondence should be addressed. E-mail: lindquist{at}wi.mit.edu

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