| Phosphorylation of α-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans. | |
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MedLine Citation:
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PMID: 22232559 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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α-Synuclein is causative for autosomal dominant familial Parkinson disease and dementia with Lewy bodies, and the phosphorylation of α-synuclein at residue Ser-129 is a key posttranslational modification detected in Parkinson disease/dementia with Lewy bodies lesions. However, the role of Ser-129 phosphorylation on the pathogenesis of Parkinson disease/dementia with Lewy bodies remains unclear. Here we investigated the neurotoxicity of Ser-129-substituted α-synuclein in the transgenic Caenorhabditis elegans (Tg worm) model of synucleinopathy. Tg worms pan-neuronally overexpressing nonphosphorylatable (S129A) α-synuclein showed severe defects including motor dysfunction, growth retardation, and synaptic abnormalities. In contrast, Tg worms expressing phosphorylation mimic (S129D) α-synuclein exhibited nearly normal phenotypes. Biochemical fractionation revealed that the level of membrane-bound α-synuclein was significantly increased in S129A-α-synuclein Tg worms, whereas S129D- as well as A30P-α-synuclein displayed lower membrane binding properties. Furthermore, A30P/S129A double mutant α-synuclein did not cause neuronal dysfunction and displayed low membrane binding property. In human neuroblastoma SH-SY5Y cells, localization of S129A-α-synuclein to membranes was significantly increased. Finally, gene expression profiling of S129A-Tg worms revealed a dramatic up-regulation of Daf-16/FOXO pathway genes, which likely act against the dysfunction caused by S129A-α-synuclein. These results imply a role of Ser-129 phosphorylation of α-synuclein in the attenuation of α-synuclein-induced neuronal dysfunction and downstream stress response by lowering the membrane binding property. |
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Authors:
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Tomoki Kuwahara; Reina Tonegawa; Genta Ito; Shohei Mitani; Takeshi Iwatsubo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-01-09 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-03-05 Completed Date: 2012-04-24 Revised Date: 2013-04-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 7098-109 Citation Subset: IM |
Affiliation:
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Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Substitution Animals Caenorhabditis elegans / genetics, metabolism* Caenorhabditis elegans Proteins / genetics, metabolism Cell Line, Tumor Cell Membrane / genetics, metabolism*, pathology Disease Models, Animal Gene Expression Profiling Humans Membrane Proteins / genetics, metabolism* Mutation, Missense* Parkinson Disease / genetics, metabolism*, pathology Phosphorylation / genetics Transcription Factors / genetics, metabolism Up-Regulation / genetics alpha-Synuclein / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Caenorhabditis elegans Proteins; 0/Membrane Proteins; 0/Transcription Factors; 0/alpha-Synuclein; 0/daf-16 protein, C elegans |
| Comments/Corrections | |
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