Characterization and targeting of a novel pathway promoting Parkinson’s Disease

项目总结/摘要 众所周知，许多与年龄相关的神经退行性疾病是由以下因素的聚集驱动的： 不正确加工或错误折叠的蛋白质。例如，α-突触核蛋白（α-Syn）在Lewy 身体导致称为共核蛋白病的一系列疾病。其中包括帕金森病 (PD)帕金森病痴呆症（Parkinson's Disease Dementia，PDD）PD和PDD中神经元丢失的机制 然而，神经炎症被认为是一种常见的特征，包括小胶质细胞活化， 在神经退行性变的早期阶段，动物模型和患者研究的证据都支持 获得性免疫反应和α-Syn反应性T细胞的参与。在本申请中，我们确定了 先前未被认识的促进α-Syn诱导的神经炎症和神经变性的途径。我们 显示该途径是由蛋白酶、组织纤溶酶原激活物（tPA）通过相互作用介导的 N-甲基-D-天冬氨酸受体-1（NMDAR 1）。使用AAV-α-Syn小鼠模型，我们发现tPA水平 在SN中，过表达α-Syn的小鼠的SN显著增加，而tPA缺乏可保护 多巴胺能神经元变性和逆转α-Syn神经毒性诱导的行为缺陷。的 tPA的作用不依赖于其蛋白水解活性，但可以通过Glunomab治疗来预防， 结合NMDAR 1并选择性抑制其与tPA相互作用的阻断抗体。tPA缺乏 和Glunomab治疗可预防神经变性，使行为正常化，减少小胶质细胞活化， 抑制T细胞浸润。基于这些初步的数据，我们将测试的假设，在响应神经元 α-Syn的过度表达或聚集增加tPA的表达通过以下途径促进神经炎症： 与NMDAR 1的相互作用和细胞毒性淋巴细胞的募集导致神经变性， 导致PD和PDD。我们将在两种不同的突触核蛋白病模型中检验这一假设，一种AAV-α-Syn 小鼠PD模型和小鼠PDD的α-syn预形成纤维（α-syn PFF）模型。

PROJECT SUMMARY/ABSTRACT It is well established that many age-related neurodegenerative diseases are driven by the aggregation of improperly processed or misfolded proteins. For example, the aggregation of α-synuclein (α-Syn) within Lewy bodies results in a constellation of diseases referred to as synucleinopathies. These include Parkinson’s Disease (PD) and Parkinson’s Disease Dementia (PDD). The mechanisms leading to neuronal loss in PD and PDD remain unknown, however, neuroinflammation is thought to be a common feature, including microglial activation in the early stages of neurodegeneration, and evidence from both animal models and patient studies supports the involvement of the adaptive immune response and α-Syn reactive T cells. In this application we identify a previously unrecognized pathway promoting α-Syn-induced neuroinflammation and neurodegeneration. We show that this pathway is mediated by the protease, tissue plasminogen activator (tPA) through an interaction with the N-methyl-D-aspartate receptor-1 (NMDAR1). Using an AAV-α-Syn mouse model we find that tPA levels in the SN are significantly increased in mice overexpressing α-Syn, and that tPA deficiency protects dopaminergic neurons from degeneration and reverses behavioral deficits induced by α-Syn neurotoxicity. The action of tPA is independent of its proteolytic activity but can be prevented by treatment with Glunomab, a blocking antibody that binds the NMDAR1 and selectively inhibits its interaction with tPA. Both tPA deficiency and Glunomab treatment prevent neurodegeneration, normalize behavior, reduce microglia activation, and inhibit T-cell infiltration. Based on these preliminary data we will test the hypothesis that in response to neuronal overexpression or aggregation of α-Syn increased expression of tPA promotes neuroinflammation through interaction with the NMDAR1 and recruitment of cytotoxic lymphocytes resulting in neurodegeneration and leading to PD and PDD. We will test this hypothesis in two different synucleinopathy models, an AAV-α-Syn mouse model of PD, and an α-syn preformed fibril (α-syn PFF) model of PDD in mice.