Molecular Mechanisms of Oxidation Resistance 1 in Parkinson's disease and Lewy Body Dementia

帕金森病和路易体痴呆中抗氧化1的分子机制

• 批准号: 10718691
• 负责人: Bobby Thomas
• 金额: $ 56.81万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718691
• 关键词: Affect; Autophagocytosis; Biochemical; C-terminal; Catalytic Domain; Cell Nucleus; Cell Survival; Cells; Clinical; Complement; Corpus striatum structure; Cytoplasmic Inclusion; DNA; Data; Defect; Dementia with Lewy Bodies; Development; Disease; Disease model; Economics; Escherichia coli; Etiology; Exhibits; Functional disorder; GTP Phosphohydrolase Activators; Genes; Genome; Glucosyltransferases; Goals; Heme; Hippocampus; Homeostasis; Human; Impaired cognition; Impairment; Inflammatory; Intervention; Knowledge; Length; Lewy Bodies; Lewy Body Dementia; Lysine; Mediating; Mediator; Metabolism; Modeling; Molecular; Molecular Target; Motor; Movement Disorders; Mus; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Onset of illness; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Process; Prosencephalon; Proteins; Proteomics; Proton Pump; Quality Control; Quality of life; Regulation; Resistance; Rodent Model; Role; Signal Transduction; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; USP6 gene; Wild Type Mouse; alpha synuclein; biological adaptation to stress; cell type; dopaminergic neuron; human data; improved; in vivo; innovation; insight; lysin; mitochondrial dysfunction; motor behavior; motor symptom; mouse model; mutant; myotubularin; neural network; neuroinflammation; neuronal survival; neuropathology; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; overexpression; oxidation; pre-clinical; pre-formed fibril; protective pathway; repaired; response; single nucleus RNA-sequencing; synucleinopathy; transcriptomics; vacuolar H+-ATPase

PROJECT SUMMARY Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of nigral dopaminergic neurons and the presence of fibrillar cytoplasmic inclusions composed of alpha-synuclein (αS) known as Lewy bodies. Neurodegeneration in PD is not limited to only the nigral dopaminergic neurons but also involves cells located in other regions of the neural network. Besides motor symptoms, cognitive impairments are one of the essential non-motor manifestations of PD that severely affects the quality of life and has substantial economic consequences. The emerging view suggests that the abnormalities in αS are a strong pathological correlate for motor and neurocognitive dysfunction in PD and Dementia with Lewy Bodies (DLB), a disease clinically and pathologically related to PD. While the mechanism by which αS pathology leads to neuronal dysfunction is unknown, existing evidence suggests that compromised redox homeostasis, defects in protein quality control, mitochondrial dysfunction, and neuroinflammation cause αS aggregation and neurodegeneration in PD and DLB. Oxidation resistance 1 (Oxr1) has emerged as a vital protein that orchestrates a multifaceted response to modulate many of the etiological pathways involved in PD and α-synucleinopathies. The mechanism underlying this process, however, remains poorly understood. Our studies show that Oxr1 overexpression is neuroprotective in preclinical PD models due to its regulation of the lysosomal proton pump vacuolar-ATPase (V-ATPase) which is critical for lysosomal function. We show that Oxr1 interacts with V-ATPase and that neurons lacking Oxr1 exhibit an increase in lysosomal pH, reduce lysosomal proteolytic activity, and exacerbate neurodegeneration in PD preclinical models. We employed innovative systems biology approaches to compare similarities in affected pathways between single-nuclei transcriptomic data from human DLB patients and proteomic data from preclinical models of α-synucleinopathy overexpressing Oxr1. Our analysis revealed that besides lysosomal pathways, Oxr1 overexpression modulated novel non-canonical pathways involved in neuronal survival due to the overabundance of pathway drivers in preclinical PD and human DLB. We hypothesize that Oxr1 is a key mediator of intrinsic protective pathways in PD and DLB. Using rodent models of α-synucleinopathy, we propose to test the hypothesis that Oxr1 overexpression ameliorates αS-induced PD and DLB by modulating both lysosomal and non-canonical neuroprotective pathways. The proposed studies will provide novel insights into molecular mechanisms underlying Oxr1-mediated neuroprotection and identify new targets for therapeutic interventions in PD and DLB.

项目摘要 帕金森病（Parkinson's disease，PD）是一种神经退行性运动障碍，其特征是黑质细胞减少， 多巴胺能神经元和存在由α-突触核蛋白（αS）组成的纤维状胞质内含物 称为路易体。PD中的神经变性不仅限于黑质多巴胺能神经元， 涉及位于神经网络其他区域的细胞。除了运动症状认知障碍 是PD的重要非运动表现之一，严重影响生活质量， 经济后果。新出现的观点表明，αS的异常是一种强烈的病理性疾病， 与PD和路易体痴呆（DLB）中的运动和神经认知功能障碍相关， 在临床和病理学上与PD相关。虽然αS病理导致神经元损伤的机制 功能障碍是未知的，现有的证据表明，受损的氧化还原稳态，蛋白质缺陷， 质量控制、线粒体功能障碍和神经炎症导致αS聚集和神经变性 在PD和DLB。抗氧化性1（Oxr 1）已经成为一种重要的蛋白质， 调节PD和α-突触核蛋白病相关的许多病因途径的反应。机制 然而，对这一过程的根本原因仍然知之甚少。我们的研究表明，Oxr 1过表达是 由于其对溶酶体质子泵空泡ATP酶的调节，在临床前PD模型中具有神经保护作用 （V-ATP酶），其对溶酶体功能至关重要。我们发现Oxr 1与V-ATPase相互作用， 缺乏Oxr 1表现出溶酶体pH升高，降低溶酶体蛋白水解活性，并加剧 PD临床前模型中的神经变性。我们采用了创新的系统生物学方法来比较 来自人类DLB患者的单核转录组数据与 来自过表达Oxr 1的α-突触核蛋白病临床前模型的蛋白质组学数据。我们的分析显示， 除了溶酶体途径外，Oxr 1过表达还调节了参与细胞凋亡的新型非经典途径。 在临床前PD和人DLB中，由于通路驱动因子的过量而导致神经元存活。我们 假设Oxr 1是PD和DLB内在保护途径的关键介质。使用啮齿动物模型， α-突触核蛋白病，我们建议测试假设Oxr 1过表达改善α S诱导的PD， DLB通过调节溶酶体和非经典神经保护途径。拟议的研究将 为Oxr 1介导的神经保护作用的分子机制提供新的见解，并确定新的 PD和DLB治疗干预的目标。