Alpha-synuclein (α-Syn) is the principal protein component of Lewy bodies, a pathological hallmark of Parkinson's disease (PD). This protein may regulate protein phosphatase 2A (PP2A) activity, although the molecular mechanisms for α-Syn-mediated regulation of PP2A and the potential neuroprotective actions of PP2A against PD-associated pathology remain largely unexplored. We found that α-Syn gene overexpression in SK-N-SH cells and primary neurons led to PP2A/C phosphorylation at Y307, a known target of Src kinase, and consequent phosphatase inhibition. In addition, phospho-activated Src (p-Y416 Src, pSrc) was higher in SK-N-SH cells and primary neurons overexpressing α-Syn. Thus, α-Syn may promote Src activation and PP2A inactivation, leading to hyperphosphorylation of proteins. Immunoprecipitation revealed higher calmodulin/Src complex formation in α-Syn-overexpressing cells and α-Syn transgenic mice. A TUNEL apoptosis assay and an MTT cell viability assay demonstrated that the PP2A activator C2-ceramide protected neurons against α-Syn-induced cell injury. Buffering the Ca(2+) elevations induced by α-Syn overexpression ameliorated the cytotoxicity of α-Syn. Our findings define a potential molecular mechanism for α-Syn-mediated regulation of PP2A through formation of the calmodulin/Src complex, activation of Src, and Src-mediated phospho-inhibition of PP2A. Overexpression of α-Syn may lead to neurodegeneration in PD in part by suppressing the endogenous neuroprotective activity of PP2A.
Alpha - synuclein ( α - Syn ) is the principal protein component of Lewy bodies , a pathological hallmark of Parkinson 's disease ( PD ) . This protein may regulate protein phosphatase 2A ( PP2A ) activity , although the molecular mechanisms for α - Syn - mediated regulation of PP2A and the potential neuroprotective actions of PP2A against PD - associated pathology remain largely unexplored . We found that α - Syn gene overexpression in SK - N - SH cells and primary neurons led to PP2A / C phosphorylation at Y307 , a known target of Src kinase , and consequent phosphatase inhibition . In addition , phospho - activated Src ( p - Y416 Src , pSrc ) was higher in SK - N - SH cells and primary neurons overexpressing α - Syn . Thus , α - Syn may promote Src activation and PP2A inactivation , leading to hyperphosphorylation of proteins . Immunoprecipitation revealed higher calmodulin / Src complex formation in α - Syn - overexpressing cells and α - Syn transgenic mice . A TUNEL apoptosis assay and an MTT cell viability assay demonstrated that the PP2A activator C2-ceramide protected neurons against α - Syn - induced cell injury . Buffering the Ca(2 + ) elevations induced by α - Syn overexpression ameliorated the cytotoxicity of α - Syn . Our findings define a potential molecular mechanism for α - Syn - mediated regulation of PP2A through formation of the calmodulin / Src complex , activation of Src , and Src - mediated phospho - inhibition of PP2A. Overexpression of α - Syn may lead to neurodegeneration in PD in part by suppressing the endogenous neuroprotective activity of PP2A.
Which is the primary protein component of Lewy bodies?
Which is the primary protein component of Lewy bodies ?
alpha-synuclein
alpha-synuclein α-synuclein αSyn