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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Alphα-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex
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Alphα-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex

机译：Alphα-突触核蛋白过表达通过形成钙调蛋白/ Src复合物增加磷酸化蛋白磷酸酶2A的水平

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摘要

Alphα-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 Ca2+ 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.
机译：Alphα-突触核蛋白（α-Syn）是路易小体的主要蛋白质成分，是帕金森氏病（PD）的病理标志。尽管α-Syn介导的PP2A调节的分子机制和PP2A对抗PD相关病理的潜在神经保护作用的分子机制，但该蛋白可能调节蛋白磷酸酶2A（PP2A）的活性。我们发现，α-Syn基因在SK-N-SH细胞和原代神经元中的过度表达导致Y307（Src激酶的已知靶标）处的PP2A / C磷酸化，并因此抑制了磷酸酶。另外，在SK-N-SH细胞和过表达α-Syn的原代神经元中，磷酸激活的Src（p-Y416 Src，pSrc）更高。因此，α-Syn可能促进Src活化和PP2A失活，导致蛋白质过度磷酸化。免疫沉淀显示在过度表达α-Syn的细胞和α-Syn转基因小鼠中钙调蛋白/ Src复合物形成更高。 TUNEL凋亡测定法和MTT细胞活力测定法表明，PP2A激活剂C2-神经酰胺可保护神经元免受α-Syn诱导的细胞损伤。缓冲由α-Syn过量表达引起的Ca2 +升高可改善α-Syn的细胞毒性。我们的发现确定了钙调蛋白/ Src复合物的形成，Src的活化和Src介导的PP2A磷酸抑制的α-Syn介导的PP2A调控的潜在分子机制。 α-Syn的过度表达可能会通过抑制PP2A的内源性神经保护活性而导致PD中的神经变性。

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