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Parkinson Disease Mutant E46K Enhances α-Synuclein Phosphorylation in Mammalian Cell Lines, in Yeast, and in Vivo

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.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 toWT 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.

Publication metadata

Author(s): Mbefo MK, Fares M-B, Paleologou K, Oueslati A, Yin G, Tenreiro S, Pinto M, Outeiro T, Zweckstetter M, Masliah E, Lashuel HA

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2015

Volume: 290

Issue: 15

Pages: 9412-9427

Online publication date: 05/02/2015

Acceptance date: 01/01/1900

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology Inc.

URL: https://doi.org/10.1074/jbc.M114.610774

DOI: 10.1074/jbc.M114.610774

PubMed id: 25657004

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