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

项目摘要/摘要 众所周知，许多与年龄相关的神经退行性疾病是由聚集的 加工不当或错误折叠的蛋白质。例如，α-突触核蛋白(α-Syn)在刘易斯内的聚集 身体会导致一系列称为联核病的疾病。其中包括帕金森氏症 帕金森氏病(PD)和帕金森氏病痴呆(PDD)。帕金森病和PDD导致神经元丢失的机制 然而，目前尚不清楚，神经炎症被认为是一个共同的特征，包括小胶质细胞的激活。 在神经退化的早期阶段，来自动物模型和患者研究的证据支持 获得性免疫反应和α-Syn反应性T细胞的参与。在此应用程序中，我们标识了一个 以前未知的促进α-Syn诱导的神经炎症和神经变性的途径。我们 表明这一途径是由蛋白酶、组织型纤溶酶原激活物(TPA)通过相互作用而介导的 与N-甲基-D-天冬氨酸受体-1(NMDAR1)结合。使用aav-α-syn小鼠模型，我们发现tPA水平 在过度表达α-syn的小鼠的SN中显著增加，tPA缺乏保护 防止多巴胺能神经元变性和逆转α-Syn神经毒性所致的行为障碍。这个 TPA的作用独立于其蛋白水解性，但可被格伦单抗预防。 与NMDAR1结合并选择性地抑制其与tPA相互作用的封闭抗体。两种tPA缺乏症 和格伦单抗治疗可防止神经退行性变，使行为正常化，减少小胶质细胞的激活，并 抑制T细胞的侵袭。基于这些初步数据，我们将检验这一假设，即对神经元的反应 α-Syn过表达或聚集tPA表达增加通过以下途径促进神经炎症 与NMDAR1的相互作用和细胞毒性淋巴细胞的募集导致神经变性和 导致帕金森病和帕金森病。我们将在两个不同的联核病模型中检验这一假设，AAV-α-SYN 小鼠帕金森病模型和α-syn预成纤维(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.