Mechanisms of alpha-synuclein mediated inflammation in multiple system atrophy

项目总结/摘要 MSA是一种进行性神经退行性疾病，由以下物质的积累和聚集引起： 少突胶质细胞中蛋白质α-突触核蛋白（α-syn）的错误折叠形式。除了神经变性和 自主神经功能障碍，最近的工作已经强调了免疫系统在疾病的病理生理学中的关键作用。 疾病在死后脑中，α-syn病理伴有HLA-DR+（MHCII）反应性小胶质细胞增生， 增加的促炎细胞因子表达和外周淋巴细胞浸润。虽然炎症 已经在人类疾病和动物模型中报道，目前尚不清楚具体是什么免疫- 介导的机制对疾病的发病机制至关重要， 保护性的 利用在少突胶质细胞中选择性过表达α-syn的新型病毒载体（Olig 001-SYN）， 已经获得了初步数据，显示了强大的炎症反应，包括MHCII+表达， 常驻的小胶质细胞和浸润的单核细胞，以及T细胞的进入，密切模拟了 人类疾病在本提案中，我将结合使用新开发的MSA Olig 001-SYN模型 用转基因小鼠和技术来剖析α-syn相关毒性的机制。具体来说，我会 剖析中枢神经系统（CNS）驻留的小胶质细胞在启动免疫应答中的作用， 通过MHCII将抗原呈递给CNS巡逻的CD 4 + T细胞，以及浸润的单核细胞和CD 4 + T细胞的作用 细胞介导脱髓鞘和神经变性。 小胶质细胞作为大脑的常驻免疫细胞，是第一个对神经损伤做出反应的细胞。在 这项建议的第一个目标，我将确定是否删除MHCII从CNS居民小胶质细胞， 保护免受α-syn-induced单核细胞和T细胞入侵，炎症，脱髓鞘， 神经变性在目标2和3中，我将确定是否使用免疫抑制剂阻断外周免疫细胞浸润， 基因缺失和药理学抑制剂减轻炎症、脱髓鞘和 在MSA的Olig 001-SYN模型中观察到的神经变性。 目前还没有减缓或阻止疾病进展的可用疗法。从长远来看，我希望 这些研究的结果将显示在临床前阶段， 空间，并且对于研究其他突触核蛋白病疾病模型中的免疫反应也将是重要的 包括帕金森病、路易体痴呆和非典型帕金森综合征。

Project Summary/Abstract MSA is a progressive neurodegenerative disorder caused by the accumulation and aggregation of misfolded forms of the protein alpha-synuclein (α-syn) in oligodendrogila. In addition to neurodegeneration and autonomic dysfunction, recent work has highlighted a key role for the immune system in the pathophysiology of disease. In postmortem brains, α-syn pathology is accompanied by HLA-DR+ (MHCII) reactive microgliosis, increased pro-inflammatory cytokine expression, and infiltration of peripheral lymphocytes. While inflammation has been reported in human disease and in animal models, it is currently unknown specifically what immune- mediated mechanisms are critical to disease pathogenesis and whether targeting those mechanisms are protective. Utilizing a novel viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN), I have obtained preliminary data showing a robust inflammatory response including MHCII+ expression on resident microglia and infiltrating monocytes, and entry of T cells closely modeling what has been reported in human disease. In this proposal, I will use this newly developed Olig001-SYN model of MSA in combination with transgenic mice and technologies to dissect the mechanisms of α-syn-related toxicity. Specifically, I will dissect the role of central nervous system (CNS) resident microglia in initiating the immune response by presenting antigen via MHCII to CNS patrolling CD4+ T cells, and the role of infiltrating monocytes and CD4 T cells in mediating demyelination and neurodegeneration. Microglia act as the resident immune cells of the brain, and are the first to respond to neural insult. In the first aim of this proposal, I will determine whether deletion of MHCII from CNS resident microglia is protective against α-syn-induced monocyte and T cell invasion, inflammation, demyelination, and neurodegeneration. In aims 2 and 3, I will determine whether blocking peripheral immune cell infiltrate using genetic deletion and pharmacological inhibitors attenuates inflammation, demyelination, and neurodegeneration observed in the Olig001-SYN model of MSA. Currently there are no available therapies that slow or halt disease progression. Long term, I hope the results from these research studies will show where to target disease-modifying therapies in the pre-clinical space, and will also be important for studying immune responses in other synucleinopathy disease models including Parkinson disease, dementia with Lewy bodies, and atypical Parkinsonisms.