Document Detail

Phosphorylation of α-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans.
MedLine Citation:
PMID:  22232559     Owner:  NLM     Status:  MEDLINE    
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.
Tomoki Kuwahara; Reina Tonegawa; Genta Ito; Shohei Mitani; Takeshi Iwatsubo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-05     Completed Date:  2012-04-24     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7098-109     Citation Subset:  IM    
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
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MeSH Terms
Amino Acid Substitution
Caenorhabditis elegans / genetics,  metabolism*
Caenorhabditis elegans Proteins / genetics,  metabolism
Cell Line, Tumor
Cell Membrane / genetics,  metabolism*,  pathology
Disease Models, Animal
Gene Expression Profiling
Membrane Proteins / genetics,  metabolism*
Mutation, Missense*
Parkinson Disease / genetics,  metabolism*,  pathology
Phosphorylation / genetics
Transcription Factors / genetics,  metabolism
Up-Regulation / genetics
alpha-Synuclein / genetics,  metabolism*
Reg. No./Substance:
0/Caenorhabditis elegans Proteins; 0/Membrane Proteins; 0/Transcription Factors; 0/alpha-Synuclein; 0/daf-16 protein, C elegans

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