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Neuron. 2015 Jan 7;85(1):76-87. doi: 10.1016/j.neuron.2014.11.027. Epub 2014 Dec 18.

Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
3
Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
4
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
5
Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
6
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.
7
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.
8
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: agitler@stanford.edu.

Erratum in

  • Neuron. 2015 Feb 4;85(3):657.

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.

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PMID:
25533483
PMCID:
PMC4289081
DOI:
10.1016/j.neuron.2014.11.027
[Indexed for MEDLINE]
Free PMC Article

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