title: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.
abstract: 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.
authors.affiliation: School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA.
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Anil
authors.initials: A
authors.lastname: Cashikar
authors.forename: Cole M
authors.initials: CM
authors.lastname: Haynes
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Hill
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bhullar
authors.forename: Kangning
authors.initials: K
authors.lastname: Liu
authors.forename: Kexiang
authors.initials: K
authors.lastname: Xu
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Songsong
authors.initials: S
authors.lastname: Cao
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Gerald
authors.initials: G
authors.lastname: Marsischky
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
authors.forename: Joshua
authors.initials: J
authors.lastname: Labaer
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: 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*
chemical_list: 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