Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.
Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn 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 alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-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.
Cooper
Antony A
AA
School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA.
Gitler
Aaron D
AD
Cashikar
Anil
A
Haynes
Cole M
CM
Hill
Kathryn J
KJ
Bhullar
Bhupinder
B
Liu
Kangning
K
Xu
Kexiang
K
Strathearn
Katherine E
KE
Liu
Fang
F
Cao
Songsong
S
Caldwell
Kim A
KA
Caldwell
Guy A
GA
Marsischky
Gerald
G
Kolodner
Richard D
RD
Labaer
Joshua
J
Rochet
Jean-Christophe
JC
Bonini
Nancy M
NM
Lindquist
Susan
S
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D004330:Drosophila; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015870:Gene Expression; D015723:Gene Library; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020761:rab1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D011506:Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D046988:Proteasome Endopeptidase Complex; C060755:YPT1 protein, S cerevisiae; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins; D004298:Dopamine