Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer’s disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology. To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients. We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls. α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

中文翻译：

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α-突触核蛋白激活经典补体途径并介导补体依赖性细胞毒性

突触核蛋白病的特征在于神经变性和突触前蛋白 α-突触核蛋白在病理性蛋白质包涵体中的沉积。越来越多的证据表明补体系统不仅在中枢神经系统中具有生理功能，而且还参与介导阿尔茨海默病中突触的病理性丧失。然而，尚未确定补体系统是否在与 α-突触核蛋白聚集体病理学相关的疾病帕金森病、路易体痴呆和多系统萎缩 (MSA) 中具有类似的作用。为了研究补体系统是否在突触核蛋白病中具有病理作用，我们评估了补体系统对 α-突触核蛋白表达细胞模型活力的影响，并在基于板的激活测定中检查了 α-突触核蛋白对补体系统的直接激活。最后，我们调查了 MSA 患者死后脑样本中经典通路起始因子 C1q 的水平。我们证明 α-突触核蛋白激活经典补体途径并介导表达 α-突触核蛋白的 SH-SY5Y 细胞中的补体依赖性毒性。补体抑制剂 RaCI（抑制 C5）和 Cp20（抑制 C3）挽救了 α-突触核蛋白依赖性细胞毒性。此外，我们观察到 MSA 受试者壳核中 C1q 水平高于对照组的趋势。α-突触核蛋白可以激活经典的补体途径，