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. VIDEO ABSTRACT:
Authors	Nripesh Dhungel, Simona Eleuteri, Ling-Bo Li, Nicholas J Kramer, Justin W Chartron, Brian Spencer, Kori Kosberg, Jerel Adam Fields, Klodjan Stafa, Anthony Adame, Hilal Lashuel, Judith Frydman, Kang Shen, Eliezer Masliah, Aaron D Gitler
Journal	Neuron (Neuron) Vol. 85 Issue 1 Pg. 76-87 (Jan 07 2015) ISSN: 1097-4199 [Electronic] United States
PMID	25533483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2015 Elsevier Inc. All rights reserved.
Chemical References	Adaptor Proteins, Vesicular Transport Caenorhabditis elegans Proteins Eif4g1 protein, mouse Eukaryotic Initiation Factor-4G Saccharomyces cerevisiae Proteins Vesicular Transport Proteins Vps35 protein, mouse alpha-Synuclein sortilin
Topics	Adaptor Proteins, Vesicular Transport Animals Caenorhabditis elegans Caenorhabditis elegans Proteins (genetics) Eukaryotic Initiation Factor-4G (genetics) Mice Mice, Transgenic Parkinson Disease (genetics) Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins (genetics) Vesicular Transport Proteins (genetics) alpha-Synuclein (genetics)

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