领导这一研究的是脑与认知科学国家重点实验室赫荣乔研究员，其早年毕业于泸州医学院，1994年曾在英国剑桥大学MRC，Bristol大学等处从事研究学习，其研究组主要研究方向是人类神经Tau结构与功能研究，除此之外还开展了脊椎动物中枢神经系统发育基因调控的研究工作，在视觉系统发育，眼睛极性的形成方面获得了一些有意义的结果。

α-突触核蛋白是一种中枢神经系统突触前表达的可溶性蛋白，帕金森病、路易体痴呆和多系统萎缩是以细胞内α-突触核蛋白沉积为特点的脑部疾病。这种蛋白在各种生理，环境因素的影响下异常表达和聚集，通过一系列的氧化应激等生化反应，产生了对神经元的毒性作用，从而参与了神经退行性疾病的发生，因此对于这一蛋白的分析研究也是解析神经退行性疾病的关键所在。

在这篇文章中，研究人员发现α-突触核蛋白的**化聚集物具细胞毒性，这种**化可以导致a-synuclein错误折叠，形成具有神经细胞毒性的聚集物。该成果阐释了**化α-突触核蛋白错误折叠聚积产物引起细胞死亡的分子机制，为突触核蛋白相关神经退行性疾病的研究提供了新的思路。

除此之外，近期来自德国、美国与加拿大的一项联合研究显示帕金森病、多系统萎缩和路易体痴呆症患者，脑脊液α-突触核蛋白浓度低于阿尔茨海默病和其他神经系统疾病患者。

脑脊液α-突触核蛋白和tau蛋白值可以从其他疾病患者中很好地区分出突触核蛋白病患者（P<0.0001，曲线下面积[AUC]=0.908）。在尸检证实的患者中，脑脊液α-突触核蛋白可区分路易体痴呆与阿尔茨海默病（P=0.0190，AUC=0.687）；在验证队列，脑脊液α-突触核蛋白可将帕金森病和路易体痴呆与进行性核上性麻痹、正常压力性脑积水以及其他神经系统疾病进行区分（P<0.0001，AUC=0.711）。脑脊液α-突触核蛋白浓度等于或低于1.6pg/μL对于帕金森病的诊断，敏感性为70.72%，特异性为52.83%。该值对于任何突触核蛋白病的阳性预测值为90.7%，阴性预测值为20.4%。

原文摘要：

A novel molecular mechanism for nitrated a-synuclein-induced cell death

Although previous studies have demonstrated the involvement of nitrated a-synuclein in neurodegenerative disorders (synucleinopathies),the effects of nitrated a-synuclein and the molecular mechanisms underlying its toxicity are still unclear. In the present study, nitrated a-synuclein with four 3-nitrotyrosines (Tyr39, Tyr125, Tyr133, and Tyr136) was obtained non-enzymatically by incubation with nitrite. The nitrated protein existed as a mixture of monomers, dimers, and polymers in solution. The nitrated a-synuclein could induce cell death in a time- and concentration-dependent manner when SH-SY5Y cells (a human neuroblastoma cell line) were incubated with the dimers and polymers. Treatment with anti-integrin a5b1 antibody partially rescued the SH-SY5Y cells from the cell death. Dot blotting and immunoprecipitation revealed that the nitrated protein bound to integrin on the cell membranes. Level of nitric oxide (NO) and calcium-independent inducible NO synthase (iNOS) activity increased during the initial stages of the treatment.
The expression of phosphorylated focal adhesion kinase (FAK) decreased in the cells. Subsequently, an increase in caspase 3
activity was observed in SH-SY5Y cells. Our results demonstrate that activation of iNOS and inhibition of FAK may both be responsible for the cell death induced by nitrated a-synuclein. These data suggest that the cytotoxicity of nitrated a-synuclein is mediated via an integrin-iNOS/-FAK signaling pathway, and that the nitration of a-synuclein plays a role in neuronal degeneration.

来源：生物通