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

促进帕金森病的新途径的表征和靶向

• 批准号: 10855706
• 负责人: Daniel A Lawrence
• 金额: $ 64.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10855706
• 关键词: Affect; Alteplase; Animal Model; Axon; Behavior; Behavioral; Bilateral; Binding; Blocking Antibodies; Brain Stem; Cells; Central Nervous System; Cerebral cortex; Cognition; Corpus striatum structure; Data; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Disease Progression; Dopamine; Dorsal; Endothelial Cells; Evaluation; Event; Exhibits; Impaired cognition; Impairment; Injections; Knock-in Mouse; Lewy Bodies; LoxP-flanked allele; Lymphocyte; Mediating; Memantine; Microglia; Modeling; Movement; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurologic; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Plasminogen Activator Interaction; Positron-Emission Tomography; Process; Proteins; Radial; Rest; Role; Signal Transduction; Site; Source; Substantia nigra structure; Synapses; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Tremor; Wild Type Mouse; adaptive immune response; age related neurodegeneration; alpha synuclein; arm; behavioral outcome; blood-brain barrier disruption; cytotoxic; dopaminergic neuron; excitotoxicity; executive function; experimental study; functional disability; glial activation; misfolded protein; motor impairment; motor symptom; mouse model; neuroinflammation; neuron loss; neurotoxicity; novel; object recognition; overexpression; pars compacta; pleiotropism; pre-formed fibril; prevent; protein aggregation; recruit; response; synucleinopathy; vesicular monoamine transporter

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.

项目概要/摘要 众所周知，许多与年龄相关的神经退行性疾病是由 蛋白质加工不当或错误折叠，例如，Lewy 内 α-突触核蛋白 (α-Syn) 的聚集。 身体会导致一系列称为突触核蛋白病的疾病，其中包括帕金森病。 (PD) 和帕金森病痴呆 (PDD) 导致 PD 和 PDD 神经元丢失的机制。 仍然未知，然而，神经炎症被认为是一个共同特征，包括小胶质细胞激活 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 适应性免疫反应和 α-Syn 反应性 T 细胞的参与在此应用中，我们确定了一种 以前未被认识的途径促进 α-Syn 诱导的神经炎症和神经变性。 表明该途径是由蛋白酶、组织纤溶酶原激活剂（tPA）通过相互作用介导的 使用 AAV-α-Syn 小鼠模型，我们发现 tPA 水平与 N-甲基-D-天冬氨酸受体-1 (NMDAR1) 相关。 在过度表达 α-Syn 的小鼠中，SN 中的 SN 显着增加，并且 tPA 缺乏可以保护 多巴胺能神经元免于退化并逆转 α-Syn 神经毒性引起的行为缺陷。 tPA 的作用与其蛋白水解活性无关，但可以通过 Glunomab（一种 结合 NMDAR1 并选择性抑制其与 tPA 相互作用的阻断抗体。 Glunomab 治疗可预防神经退行性变、使行为正常化、减少小胶质细胞激活，以及 基于这些初步数据，我们将测试神经反应的假设。 α-Syn 的过度表达或聚集增加 tPA 的表达，通过以下方式促进神经炎症： 与 NMDAR1 相互作用并招募细胞毒性淋巴细胞，导致神经变性和 我们将在两种不同的突触核蛋白病模型（AAV-α-Syn）中检验这一假设。 PD 小鼠模型，以及小鼠 PDD α-syn 预制原纤维 (α-syn PFF) 模型。