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.

项目总结 帕金森病(PD)是一种以黑质丢失为特征的神经退行性运动障碍 多巴胺能神经元和由α-突触核蛋白组成的纤维状胞浆包涵体的存在(αS) 被称为路易体。帕金森病的神经变性不仅限于黑质多巴胺能神经元，还包括 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 是严重影响生活质量的帕金森病的基本非运动性表现之一，具有实质性的 经济后果。新出现的观点表明，αS的异常是一种强烈的病理 帕金森病和路易体痴呆患者的运动和神经认知功能障碍 临床和病理上与帕金森病有关。而αS病理导致神经细胞的机制 功能障碍未知，现有证据表明，氧化还原动态平衡受损，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 在警局和德州警局。抗氧化剂1(Oxr1)是一种重要的蛋白质，可以协调多方面的 反应调节帕金森病和α-突触核病的许多致病途径。这一机制 然而，这一过程背后的原因仍然知之甚少。我们的研究表明，Oxr1的过度表达 溶酶体质子泵空泡ATPase对临床前PD模型的神经保护作用 (v-ATPase)，它是溶酶体功能的关键。我们发现Oxr1与V-ATPase相互作用，神经元 缺乏Oxr1表现出溶酶体pH升高，降低溶酶体蛋白分解活性，并加剧 帕金森病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 人类DLB患者的单核转录数据与受影响途径的相似性 过表达oxr1的α-突触核素病临床前模型的蛋白质组学数据。我们的分析显示， 除溶酶体途径外，Oxr1过表达还参与调控新的非规范途径。 临床前帕金森病和人类DLB中由于通路驱动因素过多而导致的神经元存活。我们 假设Oxr1是PD和DLB中内在保护通路的关键介体。使用啮齿动物模型 α-突触核苷酸病，我们建议检验OXr1过表达改善αS诱导的帕金森病和 通过调节溶酶体和非典型性神经保护通路。拟议的研究将 对Oxr1介导的神经保护的分子机制提供新的见解，并确定新的 帕金森病和脱氧核糖核酸治疗干预的靶点。