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.