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.

项目摘要/摘要 众所周知，许多与年龄相关的神经退行性疾病都是由聚集的 不当处理或错误折叠的蛋白质。例如，Lewy内的α-突触核蛋白（α-Syn）的聚集 身体会导致一个称为突触核断病的疾病星座。这些包括帕金森氏病 （PD）和帕金森氏病痴呆症（PDD）。导致PD和PDD神经元丧失的机制 然而，仍然未知，神经炎症被认为是一个常见特征，包括小胶质激活 在神经退行性的早期阶段，动物模型和患者研究的证据支持 自适应免疫反应和α-Syn反应性T细胞的参与。在此应用程序中，我们确定 以前无法识别的途径促进了α-Syn诱导的神经炎症和神经变性。我们 证明该途径是由蛋白酶通过相互作用的蛋白酶，组织纤溶酶原激活剂（TPA）介导的 与N-甲基-D-天冬氨酸接收器1（NMDAR1）。使用AAV-α-Syn小鼠模型，我们发现TPA水平 在过表达α-syn的小鼠中，SN显着增加，并且TPA缺乏保护 来自变性的多巴胺能神经元并逆转由α-Syn神经毒性引起的行为缺陷。这 TPA的作用与其蛋白水解活性无关，但可以通过用Glunomab治疗A来预防 阻断结合NMDAR1并有选择性抑制其与TPA的相互作用的抗体。两种TPA缺陷 Glunomab治疗可预防神经退行性，使行为正常化，减少小胶质细胞激活和 抑制T细胞浸润。基于这些初步数据，我们将检验以下假设，即响应神经元 α-Syn的过表达或聚集增加TPA的表达可促进神经炎症 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PD和PDD。我们将在两个不同的突触核力模型中检验该假设，即AAV-α-Syn PD的小鼠模型和小鼠PDD的α-Syn预制原纤维（α-Syn PFF）模型。