title: Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein.
abstract: Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and α-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nripesh
authors.initials: N
authors.lastname: Dhungel
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Eleuteri
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Li
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kramer
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Chartron
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Kori
authors.initials: K
authors.lastname: Kosberg
authors.affiliation: Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Jerel Adam
authors.initials: JA
authors.lastname: Fields
authors.affiliation: Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Klodjan
authors.initials: K
authors.lastname: Stafa
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, (EPFL) CH-1015 Lausanne, Switzerland.
authors.forename: Hilal
authors.initials: H
authors.lastname: Lashuel
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: agitler@stanford.edu.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D029742:Caenorhabditis elegans Proteins; D039603:Eukaryotic Initiation Factor-4G; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D051844:alpha-Synuclein; D000099183:Sortilin; C491908:Eif4g1 protein, mouse; C101274:Vps35 protein, mouse