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

Abstract

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.

• Authors: Tomoki Kuwahara, Reina Tonegawa, Genta Ito, Shohei Mitani, Takeshi Iwatsubo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 10 Pg. 7098-109 (Mar 02 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22232559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caenorhabditis elegans Proteins
• Forkhead Transcription Factors
• Membrane Proteins
• Transcription Factors
• alpha-Synuclein
• daf-16 protein, C elegans

Topics

• Amino Acid Substitution
• Animals
• Caenorhabditis elegans (genetics, metabolism)
• Caenorhabditis elegans Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Membrane (genetics, metabolism, pathology)
• Disease Models, Animal
• Forkhead Transcription Factors
• 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)