大鼠嗅球内病理性α-synuclein传递开启全脑水平的帕金森(PD)样神经退行性病变

Studies indicated that Lewy bodies (LBs) are the characteristic pathological markers of Parkinson's disease (PD). Autopsy results showed that it is first found in the olfactory system which accompanies the dysfunction of olfactory system. With progression of the disease, LBs were also subsequently found in the other susceptible brain regions. Once they invade the dopamine system in substantia nigra, many movement-related symptoms become apparent which lead to the clinical diagnosis of PD. LBs are known to be comprised of α-synuclein (α-syn). Transgenic animal studies have confirmed that mutant α-synuclein-A53T could simulate the pathology of PD. But it's still unclear whether α-syn in olfactory system can translocate and induce the generation of LBs in other brain regions by distance transferring. Our studies will determine whether the overexpressed α-syn via α-synuclein-A53T-AAV can translocate to vulnerable brain regions to induce the formation of LBs, in vitro and in vivo. In future studies, functional connectivity at neural circuit and system level will be examined. Our studies will explore whether α-synuclein can be transferred by a distance way and its effects will be evaluated in circuits and system levels to find a novel molecular target to prevent and cure PD.

帕金森病(PD)是以Lewy小体和中脑多巴胺神经元缺失为特征的退行性病变。病理解剖显示PD的特征性标志物Lewy小体从嗅觉系统向中脑、皮层等多个脑区蔓延,病史显示有嗅觉功能紊乱症状。α-synuclein蛋白(α-syn)是Lewy小体的主要成份，该基因的突变模拟了PD症状Lewy病变，本课题组研究显示突变型α-syn蛋白能够在细胞间近距离传递并诱导Lewy形成，但Lewy小体和神经退行性病变的因果关系及嗅觉系统进行突变型α-syn蛋白远距离传递是否可以开启退行性神经病变至今未知。本项目拟采用嗅球内注射重组α-syn-A53T-AAV诱导α-syn蛋白过表达，通过免疫荧光技术检测α-syn蛋白远距离的投射范围，同时检测黑质致密部病变情况；同时在分子、环路、系统水平上揭示α-syn蛋白传递后导致的相关脑区结构和功能变化的是空间模式，望在不同层次和尺度上提供PD发生发展机制的信息。

帕金森病(PD)是以Lewy小体和中脑多巴胺神经元缺失为特征的退行性病变。病理解剖显示PD的特征性标志物Lewy小体从嗅觉系统向中脑、皮层等多个脑区蔓延,病史显示有嗅觉功能紊乱症状。α-synuclein蛋白(α-syn)是Lewy小体的主要成份，该基因的突变模拟了PD症状Lewy病变，本课题组研究显示突变型α-syn蛋白能够在细胞间近距离传递并诱导Lewy形成，但Lewy小体和神经退行性病变的因果关系及嗅觉系统进行突变型α-syn蛋白远距离传递是否可以开启退行性神经病变至今未知。1）本研究以嗅球内注射重组突变型α-synuclein-A53T-GFP-AAV诱导α-synuclein -GFP蛋白表达通过嗅觉系统进行远距离传递到易感脑区诱导Lewy小体形成，黑质致密部多巴胺神经元是否受损。α-synuclein–GFP通过嗅觉进行远距离传递后，诱导易感脑区神经元的形态、结构、连接等方面发生紊乱，该研究从一个全新的角度证实alpha-synuclein是PD病变的靶向分子，研究成果发表在《translational neruodegeration》(影响因子5.8)，为筛选抗帕金森病药物提供了基础数据支持。2）研究中发现嗅觉炎症在诱导alpha-synuclein发生病变过程中发挥着重要作用，LPS鼻腔滴注诱导嗅觉系统炎症能够诱导alpha-synuclein的表达，Micorglia释放IL-1β与僧帽细胞上IL-1R1结合诱导alpha-synuclein的过表达后进而引发该蛋白发生聚集化，形成具有生物毒性、能够在神经细胞之间传递的小分子，诱导正常alpha-Synuclein形成异常的聚集状态的alpha-synuclein。通过系统的探讨α-synuclein蛋白通过嗅觉神经投射进行远距离传递诱导Lewy小体的机制及其对神经功能的影响，为PD病变的发生、治疗和预防提供全新的视角，并探讨α-synuclein蛋白远距离传递的分子机制，为药物治疗PD提供候选靶点。