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.

项目总结/文摘