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

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.

doi:10.1074/jbc.M114.610774

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

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Yin, G.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter, M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Citation

Mbefo, M. K., Fares, M. B., Paleologou, K., Oueslati, A., Yin, G., Tenreiro, S., et al. (2015). Parkinson disease mutant E46K enhances alpha-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo. Journal of Biological Chemistry, 290(15), 9412-9427. doi:10.1074/jbc.M114.610774.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0026-C6A0-1

Abstract

Although alpha-synuclein (alpha-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 alpha-syn phosphorylation. In this study, we investigated the effects of the A30P, E46K, and A53T PD-linked mutations on alpha-syn phosphorylation at residues Ser-87 and Ser-129. Although the A30P and A53T mutants slightly affected Ser(P)-129 levels compared with WT alpha-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 alpha-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.