Phosphorylation of ?-synuclein protein at Ser-129 reduces neuronal dysfunction by lowering its membrane binding property in Caenorhabditis elegans.

ABSTRACT: ?-Synuclein is causative for autosomal dominant familial Parkinson disease and dementia with Lewy bodies, and the phosphorylation of ?-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 ?-synuclein in the transgenic Caenorhabditis elegans (Tg worm) model of synucleinopathy. Tg worms pan-neuronally overexpressing nonphosphorylatable (S129A) ?-synuclein showed severe defects including motor dysfunction, growth retardation, and synaptic abnormalities. In contrast, Tg worms expressing phosphorylation mimic (S129D) ?-synuclein exhibited nearly normal phenotypes. Biochemical fractionation revealed that the level of membrane-bound ?-synuclein was significantly increased in S129A-?-synuclein Tg worms, whereas S129D- as well as A30P-?-synuclein displayed lower membrane binding properties. Furthermore, A30P/S129A double mutant ?-synuclein did not cause neuronal dysfunction and displayed low membrane binding property. In human neuroblastoma SH-SY5Y cells, localization of S129A-?-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-?-synuclein. These results imply a role of Ser-129 phosphorylation of ?-synuclein in the attenuation of ?-synuclein-induced neuronal dysfunction and downstream stress response by lowering the membrane binding property.

SUBMITTER: Kuwahara T 

PROVIDER: S-EPMC3293593 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature