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  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., 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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0026-C6A0-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-1C96-A
Genre: Journal Article

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Mbefo, M. K., Author
Fares, M. B., Author
Paleologou, K., Author
Oueslati, A., Author
Yin, G.1, Author              
Tenreiro, S., Author
Pinto, M., Author
Outeiro, T., Author
Zweckstetter, M.2, Author              
Masliah, E., Author
Lashuel, H. A., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 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.

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Language(s): eng - English
 Dates: 2015-02-052015-04-10
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M114.610774
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 290 (15) Sequence Number: - Start / End Page: 9412 - 9427 Identifier: -