title: The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis.
abstract: alpha-Synuclein (alpha-syn), a protein of unknown function, is the most abundant protein in Lewy bodies, the histological hallmark of Parkinson's disease (PD). In yeast alpha-syn inhibits endoplasmic reticulum (ER)-to-Golgi (ER-->Golgi) vesicle trafficking, which is rescued by overexpression of a Rab GTPase that regulates ER-->Golgi trafficking. The homologous Rab1 rescues alpha-syn toxicity in dopaminergic neuronal models of PD. Here we investigate this conserved feature of alpha-syn pathobiology. In a cell-free system with purified transport factors alpha-syn inhibited ER-->Golgi trafficking in an alpha-syn dose-dependent manner. Vesicles budded efficiently from the ER, but their docking or fusion to Golgi membranes was inhibited. Thus, the in vivo trafficking problem is due to a direct effect of alpha-syn on the transport machinery. By ultrastructural analysis the earliest in vivo defect was an accumulation of morphologically undocked vesicles, starting near the plasma membrane and growing into massive intracellular vesicular clusters in a dose-dependent manner. By immunofluorescence/immunoelectron microscopy, these clusters were associated both with alpha-syn and with diverse vesicle markers, suggesting that alpha-syn can impair multiple trafficking steps. Other Rabs did not ameliorate alpha-syn toxicity in yeast, but RAB3A, which is highly expressed in neurons and localized to presynaptic termini, and RAB8A, which is localized to post-Golgi vesicles, suppressed toxicity in neuronal models of PD. Thus, alpha-syn causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive.
authors.affiliation: Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, Cambridge, MA 02142, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Brooke J
authors.initials: BJ
authors.lastname: Bevis
authors.forename: James
authors.initials: J
authors.lastname: Shorter
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Shusei
authors.initials: S
authors.lastname: Hamamichi
authors.forename: Linhui Julie
authors.initials: LJ
authors.lastname: Su
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Charles
authors.initials: C
authors.lastname: Barlowe
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D001692:Biological Transport; D017173:Caenorhabditis elegans; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020826:rab3A GTP-Binding Protein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins; D020826:rab3A GTP-Binding Protein