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

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

The Journal of biological chemistry (2015-02-07)
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
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.

MATERIALS
Product Number
Brand
Product Description

Millipore
ProteoExtract® Subcellular Proteome Extraction Kit
Sigma-Aldrich
Anti-Synuclein α Antibody, Chemicon®, from sheep