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

Martial Kamdem Mbefo, Mohamed Bilal Fares, Katerina Paleologou, Abid Oueslati, Guowei Yin, Sandra Tenreiro, Madalena Pinto, Tiago Outeiro, Markus Zweckstetter, Eliezer Masliah, Hilal A. Lashuel

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27 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)9412-9427
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number15
DOIs
Publication statusPublished - 10 Apr 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mbefo, M. K., Fares, M. B., Paleologou, K., Oueslati, A., Yin, G., Tenreiro, S., Pinto, M., Outeiro, T., Zweckstetter, M., Masliah, E., & Lashuel, H. A. (2015). Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo. Journal of Biological Chemistry, 290(15), 9412-9427. https://doi.org/10.1074/jbc.M114.610774