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: 10805594
• 负责人: Rita Marie Cowell
• 金额: $ 55.71万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/10805594
• 关键词: Acute; Age; Aging; Astrocytes; Autopsy; Behavior; Bioinformatics; Biological Availability; Brain; Cells; Cellular Stress; Characteristics; DNA Repair; Data; Disease; Dopamine; Down-Regulation; Enzymes; Equilibrium; Etiology; Evaluation; Exhibits; Extracellular Space; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genetic Variation; Health; Heterozygote; Homeostasis; Human; Immune; Impairment; Inflammation; Inflammatory; Inherited; Injections; Knockout Mice; Laboratories; Lewy Bodies; Lewy neurites; Link; Lipopolysaccharides; Maintenance; Mediator; 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; Testing; Tissues; Transcript; Vesicle; Work; alpha synuclein; carbohydrate metabolism; cell type; disorder risk; dopaminergic neuron; experimental study; extracellular; genome wide association study; immune cell infiltrate; insight; mRNA Expression; mitochondrial dysfunction; mouse model; neuron loss; neuronal survival; neuropathology; 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 关于胶质细胞失调和炎症在发病机制中的作用存在争议 帕金森病（PD）在PD患者的死后组织中检测到炎症迹象， 最近的证据表明，与家族性PD相关的基因突变可以影响PD的功能， 星形胶质细胞和小胶质细胞。这些发现，加上PD患者HLA基因座突变的存在， 患者，导致研究人员提出炎症和神经胶质功能障碍在PD中的病因作用。 然而，炎症、胶质细胞失调和神经胶质细胞增殖之间的机制联系缺乏直接证据。 PD的神经元损失特征。 为了鉴定胶质细胞中PD相关过程的潜在细胞自主介质，我们使用生物信息学方法， 这是一种鉴定小鼠脑神经胶质细胞中富集的PD GWAS基因的策略。有趣的是， 基因在星形胶质细胞中表现出丰富的表达。PD连锁的单核苷酸多态性， 这些基因，CD 38，与人脑中CD 38转录本表达的~45%减少有关。 以前的工作已经证明了CD 38在外周免疫细胞中的作用，在那里它可以调节REDOX 在细胞内和细胞外室的平衡; CD 38在大脑中的作用只是最近才被发现。 探讨了我们实验室的初步实验表明，CD 38的表达是富集的， 在人和小鼠脑的星形胶质细胞中，NAD/NAM平衡在CD 38的各个区域被破坏， 敲除小鼠脑，炎症和CD 38缺陷协同相互作用影响运动功能。 在这里，我们建议使用CD 38作为一个原型基因，以了解神经胶质功能障碍的方式可以给 通过研究1）在维持REDOX中对CD 38的需求， 稳态和多巴胺能神经元的功能和活力，2）CD 38在调节中的作用 黑质炎症的影响，以及3）CD 38调节对多巴胺能神经元脆弱性的影响。 两种突触核蛋白病小鼠PD模型中的神经元。一组实验将测试 通过确定是否提供CD 38-缺陷小鼠中观察到的变化中的REDOX失调， 烟酰胺核苷，一种生物可利用的NAD前体，可以预防多巴胺能氧化应激，细胞功能障碍， 和失去总而言之，这些实验有可能揭示增加的机械贡献者。 神经元的脆弱性与神经胶质功能障碍，并提供新的信息，神经胶质细胞在维持 多巴胺能神经元在衰老和疾病中的存活。