Glial Involvement in REDOX Homeostasis in the Substantia Nigra

胶质细胞参与黑质氧化还原稳态

• 批准号: 10307017
• 负责人: Rita Marie Cowell
• 金额: $ 66.59万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307017
• 关键词: Acute; Age; Aging; Astrocytes; Autopsy; Behavior; Bioavailable; Bioinformatics; Brain; Cells; Cellular Stress; Characteristics; DNA Repair; Data; Disease; Dopamine; Down-Regulation; Encephalitis; Enzymes; Equilibrium; Etiology; Evaluation; Exhibits; Extracellular Space; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genetic Variation; Health; Homeostasis; Human; Immune; Impairment; Infiltration; Inflammation; Inflammatory; Inherited; Injections; Knockout Mice; Laboratories; Lewy Bodies; Lewy neurites; Link; Lipopolysaccharides; Maintenance; Mediator of activation protein; Messenger RNA; Microglia; Mitochondria; Modeling; Motor; Movement Disorders; Mus; Mutation; Neuroglia; Neurologic; Neurons; Niacinamide; Nicotinamide adenine dinucleotide; Ontology; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Process; Production; Proteins; Quantitative Trait Loci; Reaction; Regulation; Research Personnel; Role; Single Nucleotide Polymorphism; Sirtuins; Source; Substantia nigra structure; Synapses; Synaptic Vesicles; Testing; Time; Tissues; Transcript; Work; alpha synuclein; base; carbohydrate metabolism; cell type; disorder risk; dopaminergic neuron; experimental study; genome wide association study; insight; mRNA Expression; mitochondrial dysfunction; mouse model; neuron loss; neurotransmitter release; nicotinamide-beta-riboside; novel; prevent; reconstitution; response; risk variant; synaptic function; synucleinopathy; trafficking

PROJECT SUMMARY Controversies exist regarding the contribution of glial cell dysregulation and inflammation to the pathogenesis of Parkinson Disease (PD). Signs of inflammation have been detected in postmortem tissue of PD patients, and recent evidence suggests that mutations in genes associated with familial PD can influence the function of astrocytes and microglia. These findings, together with the existence of mutations in the HLA locus in PD patients, have led investigators to propose an etiological role for inflammation and glial dysfunction in PD. However, direct evidence is lacking for mechanistic links among inflammation, glial dysregulation, and the neuronal loss characteristic of PD. To identify potential cell-autonomous mediators of PD-relevant processes in glia, we used a bioinformatics strategy to identify PD GWAS genes enriched in glial cells of the mouse brain. Interestingly, a small subset of genes exhibits enrichment of expression in astrocytes. PD-linked single-nucleotide polymorphisms in one of these genes, CD38, are associated with a ~45% reduction in CD38 transcript expression in the human brain. Previous work has demonstrated a role for CD38 in peripheral immune cells, where it serves to regulate REDOX balance in both intra- and extra-cellular compartments; the roles for CD38 in the brain have only recently been explored. Preliminary experiments from our laboratory have shown that CD38 expression is enriched in astrocytes of the human and mouse brain, NAD/NAM balance is disrupted in various regions of the CD38 knockout mouse brain, and inflammation and CD38 deficiency synergistically interact to influence motor function. Here, we propose to use CD38 as a prototypical gene to understand ways in which glial dysfunction can give rise to a PD-like phenotype in mice by investigating 1) the requirement for CD38 in the maintenance of REDOX homeostasis and dopaminergic neuron function and viability in aging mice, 2) the role for CD38 in the regulation of inflammation in the substantia nigra, and 3) the impact of CD38 modulation on the vulnerability of dopaminergic neurons in two synucleinopathy mouse models of PD. A subset of experiments will test the involvement of REDOX dysregulation in the changes observed in CD38-deficient mice by determining whether provision of nicotinamide riboside, a bioavailable NAD precursor, can prevent dopaminergic oxidative stress, cell dysfunction, and loss. Altogether, these experiments have the potential to reveal mechanistic contributors to increased neuronal vulnerability with glial dysfunction and provide novel information about the roles for glia in maintaining dopaminergic neuron survival in aging and disease.

项目摘要 关于神经胶质细胞失调和炎症对发病机理的贡献存在争议 帕金森氏病（PD）。在PD患者的死后组织中已经检测到炎症的迹象， 最近的证据表明，与家族性PD相关的基因突变会影响 星形胶质细胞和小胶质细胞。这些发现，加上PD中HLA基因座中的突变 患者已导致研究人员提出了PD炎症和神经胶质功能障碍的病因作用。 然而，缺乏直接证据表明炎症，神经胶质失调和 PD的神经元损失特征。 为了鉴定PD相关过程中潜在的细胞自主介质，我们使用了生物信息学 鉴定富含小鼠脑神经胶质细胞的PD GWAS基因的策略。有趣的是，一小部分 基因在星形胶质细胞中表现出富集。 PD连接的单核苷酸多态性之一 这些基因CD38与人脑的CD38转录本表达降低约45％。 以前的工作已经证明了CD38在外周种免疫细胞中的作用，在该细胞中它用于调节氧化还原 在细胞内和细胞外室的平衡； CD38在大脑中的作用直到最近才是 探索。我们实验室的初步实验表明，CD38表达富含 人类和小鼠大脑的星形胶质细胞，NAD/NAM平衡在CD38的各个区域被破坏 敲除小鼠脑，炎症和CD38缺乏协同相互作用以影响运动功能。 在这里，我们建议将CD38用作原型基因，以了解神经胶质功能障碍的方法 通过研究1）在维持氧化还原方面对CD38的需求提升到小鼠中的PD样表型 稳态和多巴胺能神经元功能和衰老小鼠的生存力，2）CD38在调节中的作用 黑质中的炎症，以及3）CD38调节对多巴胺能的脆弱性的影响 PD的两种突触核力病小鼠模型中的神经元。一部分实验将测试 通过确定是否提供了是否提供 烟酰胺核苷是一种可生物利用的NAD前体，可以预防多巴胺能氧化应激，细胞功能障碍， 和损失。总的来说，这些实验有可能揭示机械贡献者的增加 神经元脆弱性具有神经胶质功能障碍，并提供有关神经胶质作用的新信息 多巴胺能神经元在衰老和疾病中的生存。