title: Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo.
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.
authors: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland.
authors: Martial Kamdem
authors: MK
authors: Mbefo
authors: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland.
authors: Mohamed-Bilal
authors: MB
authors: Fares
authors: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland.
authors: Katerina
authors: K
authors: Paleologou
authors: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Station 15, 1015 Lausanne, Switzerland.
authors: Abid
authors: A
authors: Oueslati
authors: the Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors: Guowei
authors: G
authors: Yin
authors: the Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, and.
authors: Sandra
authors: S
authors: Tenreiro
authors: the Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, and.
authors: Madalena
authors: M
authors: Pinto
authors: the 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.
authors: Tiago
authors: T
authors: Outeiro
authors: the 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.
authors: Markus
authors: M
authors: Zweckstetter
authors: the Departments of Pathology and Neurosciences, School of Medicine, University of California at San Diego, San Diego, California 92103.
authors: Eliezer
authors: E
authors: Masliah
authors: From 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.
authors: Hilal A
authors: HA
authors: Lashuel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D012694:Serine / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D012694:Serine; C496126:PLK2 protein, human; D047389:Casein Kinase I; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: A30P; A53T; E46K; Nuclear Translocation; Parkinson Disease; Post-translational Modification; Protein Phosphorylation; α-Synuclein
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