來自中國科學院生物物理研究所腦與認知科學國家重點實驗室的研究人員發(fā)現(xiàn)一種與神經(jīng)退行性疾病密切相關的蛋白——突觸核蛋白α-synuclein的硝基化聚集物具細胞毒性,，這為突觸核蛋白相關神經(jīng)退行性疾病的研究提供了新的思路,。這一研究成果公布在《分子細胞生物學期刊》（J Mol Cell Biol）上。
領導這一研究的是腦與認知科學國家重點實驗室赫榮喬研究員,，其早年畢業(yè)于瀘州醫(yī)學院，1994年曾在英國劍橋大學MRC,，布里斯托爾大學等處從事研究學習,，其研究組主要研究方向是人類神經(jīng)Tau結構與功能研究，除此之外還開展了脊椎動物中樞神經(jīng)系統(tǒng)發(fā)育基因調(diào)控的研究工作,，在視覺系統(tǒng)發(fā)育,、眼睛極性的形成方面獲得了一些有意義的結果。
α-突觸核蛋白是一種中樞神經(jīng)系統(tǒng)突觸前表達的可溶性蛋白,，帕金森病,、路易體癡呆和多系統(tǒng)萎縮是以細胞內(nèi)α-突觸核蛋白沉積為特點的腦部疾病。這種蛋白在各種生理,，環(huán)境因素的影響下異常表達和聚集,，通過一系列的氧化應激等生化反應，產(chǎn)生了對神經(jīng)元的毒性作用,，從而參與了神經(jīng)退行性疾病的發(fā)生,，因此對于這一蛋白的分析研究也是解析神經(jīng)退行性疾病的關鍵所在。
在這篇文章中,，研究人員發(fā)現(xiàn)α-突觸核蛋白的硝基化聚集物具細胞毒性,，這種硝基化可以導致a-synuclein錯誤折疊，形成具有神經(jīng)細胞毒性的聚集物,。該成果闡釋了硝基化α-突觸核蛋白錯誤折疊聚積產(chǎn)物引起細胞死亡的分子機制,，為突觸核蛋白相關神經(jīng)退行性疾病的研究提供了新的思路。
除此之外,，近期來自德國,、美國與加拿大的一項聯(lián)合研究顯示帕金森病、多系統(tǒng)萎縮和路易體癡呆癥患者,，腦脊液α-突觸核蛋白濃度低于阿爾茨海默病和其他神經(jīng)系統(tǒng)疾病患者,。
腦脊液α-突觸核蛋白和tau蛋白值可以從其他疾病患者中很好地區(qū)分出突觸核蛋白病患者（P<0.0001，曲線下面積[AUC]=0.908）,。在尸檢證實的患者中,，腦脊液α-突觸核蛋白可區(qū)分路易體癡呆與阿爾茨海默病（P=0.0190,，AUC=0.687）,；在驗證隊列，腦脊液α-突觸核蛋白可將帕金森病和路易體癡呆與進行性核上性麻痹,、正常壓力性腦積水以及其他神經(jīng)系統(tǒng)疾病進行區(qū)分（P<0.0001,，AUC=0.711）。腦脊液α-突觸核蛋白濃度等于或低于1.6pg/μL對于帕金森病的診斷,，敏感性為70.72%,，特異性為52.83%,。該值對于任何突觸核蛋白病的陽性預測值為90.7%，陰性預測值為20.4%,。(生物谷 Bioon.com)
生物谷推薦原文出處：
J Mol Cell Biol doi: 10.1093/jmcb/mjr011
A novel molecular mechanism for nitrated α-synuclein-induced cell death
Yanying Liu, Min Qiang, Yan Wei1 and Rongqiao He
Although previous studies have demonstrated the involvement of nitrated α-synuclein in neurodegenerative disorders (synucleinopathies), the effects of nitrated α-synuclein and the molecular mechanisms underlying its toxicity are still unclear. In the present study, nitrated α-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 α-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 α5β1 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 α-synuclein. These data suggest that the cytotoxicity of nitrated α-synuclein is mediated via an integrin-iNOS/-FAK signaling pathway, and that the nitration of α-synuclein plays a role in neuronal degeneration.
