α-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, Katharine 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, Susan Lindquist

Research output: Contribution to journalArticle

902 Scopus citations

Abstract

Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn 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 αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-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.

Original languageEnglish (US)
Pages (from-to)324-328
Number of pages5
JournalScience
Volume313
Issue number5785
DOIs
StatePublished - Jul 21 2006
Externally publishedYes

ASJC Scopus subject areas

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    Cooper, A. A., Gitler, A. D., Cashikar, A., Haynes, C. M., Hill, K. J., Bhullar, B., Liu, K., Xu, K., Strathearn, K. E., Liu, F., Cao, S., Caldwell, K. A., Caldwell, G. A., Marsischky, G., Kolodner, R. D., LaBaer, J., Rochet, J. C., Bonini, N. M., & Lindquist, S. (2006). α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science, 313(5785), 324-328. https://doi.org/10.1126/science.1129462