TY - JOUR
T1 - α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models
AU - Cooper, Antony A.
AU - Gitler, Aaron D.
AU - Cashikar, Anil
AU - Haynes, Cole M.
AU - Hill, Kathryn J.
AU - Bhullar, Bhupinder
AU - Liu, Kangning
AU - Xu, Kexiang
AU - Strathearn, Katharine E.
AU - Liu, Fang
AU - Cao, Songsong
AU - Caldwell, Kim A.
AU - Caldwell, Guy A.
AU - Marsischky, Gerald
AU - Kolodner, Richard D.
AU - LaBaer, Joshua
AU - Rochet, Jean Christophe
AU - Bonini, Nancy M.
AU - Lindquist, Susan
PY - 2006/7/21
Y1 - 2006/7/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33746533924&partnerID=8YFLogxK
U2 - 10.1126/science.1129462
DO - 10.1126/science.1129462
M3 - Article
C2 - 16794039
AN - SCOPUS:33746533924
SN - 0036-8075
VL - 313
SP - 324
EP - 328
JO - Science
JF - Science
IS - 5785
ER -