Mbefo, Martial KamdemFares, Mohamed-BilalPaleologou, KaterinaOueslati, AbidYin, GuoweiTenreiro, SandraPinto, MadalenaOuteiro, TiagoZweckstetter, MarkusMasliah, EliezerLashuel, Hilal A2015-02-172015-02-172015-02-17201510.1074/jbc.M114.610774https://infoscience.epfl.ch/handle/20.500.14299/111025WOS:000352729400010Although 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.Mutationtext::journal::journal article::research article