基于α-突触核蛋白"朊蛋白样"传播的帕金森病发病新机制的研究

Our earlier post-mortem analyses of brains from patients with Parkinson’s disease (PD) who received fetal mesencephalic transplants showed that α-synuclein-containing Lewy bodies gradually appear in grafted neurons. We recently showed evidence of α-synuclein cell-to-cell transfer using in vitro and in vivo models of PD, indicating that intercellular transfer of alpha-synuclein from host to graft, using a prion-like mechanism, by seeding of α-synuclein aggregation in recipient neurons, This has opened a new avenue to study the pathogenic mechanisms of PD from a completely different angle.. In this project we will elucidate mechanisms underlying intercellular α-synuclein transfer and transport and examine if they play a role in PD pathogenesis. Using combined interdisciplinary technologies, including in vivo two photon imaging, super-resolution imaging, stem cell biology, neural transplantation, protein chemistry, transgenics, and invertebrate (drosophila) biology we will specifically address following key issues: how aggregated α-synuclein is transmitted between cells, crossing synapses and how it is transported along neural processes, axon and dendrites; how misfolded α-synuclein acts as a seed to endogenous α-synuclein of the recipient cells; and how the recipient cells respond to the transferred α-synuclein, and finally seeking for potential small molecules to inhibit the processes of α-synuclein spread.. The fulfillment of the proposed project will provide completely novel insight into the principles governing how neuropathological changes spread in the brains of PD patients. The findings in PD on cell-to-cell transmission and transport of misfolded proteins might also be relevant to several neurodegenerative disorders and open a new way of therapeutic intervention to PD and the related diseases..

近期，申请者及其他团队的开拓性研究发现，引起帕金森病 (PD) 神经病变的关键蛋白α-突触核蛋白 (α-Syn) 可在PD患者脑内神经元之间进行“朊蛋白样”传播，导致多巴胺能神经元功能丧失。然而，对α-Syn如何在神经细胞间传播，是否对“受染细胞”产生“种子效应”启动内源性α-Syn的病理性聚集等一系列科学问题尚未解决。为此，本项目拟通过超高分辨成像、双光子激光扫描技术结合α-Syn转基因小鼠、果蝇和细胞模型等，明确致病蛋白α-Syn在细胞间的“朊蛋白样”传播、跨突触传递、远距离运输的途径，阐明“受染细胞”对外源性c-Syn“种子效应”的应激反应及其分子机制，同时筛选对α-Syn神经细胞间传播和聚集具有抑制作用的小分子化合物和特异性抗体，建立有效的PD干预措施，为引领新的PD研究方向以及对创造具有自主知识产权的PD防治新策略提供科学依据和新思路。

帕金森病 (Parkinson’s disease, PD)是一常见的神经退行性疾病。PD患者的主要临床表现有运动功能障碍，同时可伴随有各种的非运动症状。PD的典型病理特征为中脑多巴胺神经细胞死亡及细胞内阿尔法-突触核蛋白(a-Syn)错误折叠形成蛋白聚集体 – 路易小体。对于PD，临床上仍没有可治愈的有效手段，多仅仅是对症治疗。迄今，对PD的发生、发展仍了解甚少。基于此，我们针对PD发病过程中蛋白质病理性聚集及传播这一核心问题，利用多种细胞及动物，结合蛋白质化学、细胞及组织化学、干细胞分化及（活细胞）显微成像等技术，研究其分子及细胞生物学机理以及由此造成的神经功能障碍，并探索可能的干预手段。我们的研究结果表明： 1）PD病理变化（如， a-Syn聚集及磷酸化）在胃肠神经系统随年龄的增长而加重，并与肠道炎症相关；外源性a-Syn可从胃肠神经丛或交感神经节向脑内传播，且影响效应器官的功能；脑内a-Syn聚集体的清除与脑膜类淋巴系统的引流高度相关； 2）a-Syn的病变可循顺行及逆向运输沿轴突/树突远距离传播；3）a-Syn的聚集及传播可以诱发多种神经功能紊乱，如突触可塑性、线粒体功能及神经生成的改变；4）小分子化合物二氢杨梅素丹酚酸B，以及降低铜离子浓度可以抑制a-Syn的聚集。本项目的实施加深了我们对PD发病机制的理解，为PD的预防和治疗开辟新途径，并为研发阻止PD病情进展的新药提供了理论基础和新的思路。