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J Biol Chem. 2015 Apr 10;290(15):9412-27. doi: 10.1074/jbc.M114.610774. Epub 2015 Feb 5.

Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo.

Author information

  • 1From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland.
  • 2the Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
  • 3the Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, and.
  • 4the Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, and Instituto de Fisiologia, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz 1649-028 Lisboa, Portugal, the Department of NeuroDegeneration and Restorative Research, University Medical Center Goettingen and.
  • 5the Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, the German Center for Neurodegenerative Diseases, Am Fassberg 11, 37077 Göttingen, Germany, and.
  • 6the Departments of Pathology and Neurosciences, School of Medicine, University of California at San Diego, San Diego, California 92103.
  • 7From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland, hilal.lashuel@epfl.ch.

Abstract

Although α-synuclein (α-syn) phosphorylation has been considered as a hallmark of sporadic and familial Parkinson disease (PD), little is known about the effect of PD-linked mutations on α-syn phosphorylation. In this study, we investigated the effects of the A30P, E46K, and A53T PD-linked mutations on α-syn phosphorylation at residues Ser-87 and Ser-129. Although the A30P and A53T mutants slightly affected Ser(P)-129 levels compared with WT α-syn, the E46K mutation significantly enhanced Ser-129 phosphorylation in yeast and mammalian cell lines. This effect was not due to the E46K mutant being a better kinase substrate nor due to alterations in endogenous kinase levels, but was mostly linked with enhanced nuclear and endoplasmic reticulum accumulation. Importantly, lentivirus-mediated overexpression in mice also showed enhanced Ser-129 phosphorylation of the E46K mutant compared to WT α-syn, thus providing in vivo validation of our findings. Altogether, our findings suggest that the different PD-linked mutations may contribute to PD pathogenesis via different mechanisms.

KEYWORDS:

A30P; A53T; E46K; Nuclear Translocation; Parkinson Disease; Post-translational Modification; Protein Phosphorylation; α-Synuclein

PMID:
25657004
PMCID:
PMC4392248
DOI:
10.1074/jbc.M114.610774
[PubMed - indexed for MEDLINE]
Free PMC Article
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