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• W2023875044 endingPage "9427" @default.
• W2023875044 startingPage "9412" @default.
• W2023875044 abstract "Background: Little is known about the effect of PD-linked mutations on α-synuclein (α-syn) phosphorylation.Results: The E46K mutation increases α-syn phosphorylation at Ser-129 and influences its subcellular localization in vivo.Conclusion: The E46K mutation alters α-syn localization and post-translational modifications.Significance: PD-linked α-syn mutations may contribute to PD via different mechanisms.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. Background: Little is known about the effect of PD-linked mutations on α-synuclein (α-syn) phosphorylation. Results: The E46K mutation increases α-syn phosphorylation at Ser-129 and influences its subcellular localization in vivo. Conclusion: The E46K mutation alters α-syn localization and post-translational modifications. Significance: PD-linked α-syn mutations may contribute to PD via different mechanisms. 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." @default.
• W2023875044 created "2016-06-24" @default.
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• W2023875044 date "2015-04-01" @default.
• W2023875044 modified "2023-10-02" @default.
• W2023875044 title "Parkinson Disease Mutant E46K Enhances α-Synuclein Phosphorylation in Mammalian Cell Lines, in Yeast, and in Vivo" @default.
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• W2023875044 doi "https://doi.org/10.1074/jbc.m114.610774" @default.
• W2023875044 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4392248" @default.
• W2023875044 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25657004" @default.

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