Functional analysis of glia in alpha-synucleinopathy

α-突触核蛋白病中神经胶质细胞的功能分析

• 批准号: 9460151
• 负责人: MEL B FEANY
• 金额: $ 26.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460151
• 关键词: Adult; Aging; Biochemical Pathway; Biological Models; Biology; Bradykinesia; Brain; Clinical; Complex; Cytoplasmic Inclusion; Deposition; Development; Diffuse; Disease; Drosophila genus; Experimental Genetics; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Gliosis; Human; Impaired cognition; Lewy Bodies; Lewy Body Dementia; Longevity; Mediating; Methodological Studies; Modeling; Molecular; Molecular Genetics; Molecular Target; Morphology; Movement Disorders; Multiple System Atrophy; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neurologist; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Play; Point Mutation; Population; Process; Proteins; Risk; Risk Factors; Role; Somatotype; Synapses; System; Testing; Toxic effect; Tremor; alpha synuclein; alpha synuclein gene; base; cellular targeting; design; dopaminergic neuron; early onset; gene product; genetic approach; genetic association; genetic risk factor; genome wide association study; genome-wide; innovation; molecular array; nervous system disorder; neuropathology; neurotoxicity; non-motor symptom; novel; protein aggregate; synucleinopathy; therapy development; tool

Parkinson's disease is the most common movement disorder and is characterized clinically by tremor and bradykinesia, as well as by cognitive decline in more widespread forms of the disease. Classic neuropathological features of Parkinson's disease include intraneuronal Lewy bodies formed by intraneuronal deposition of abnormally phosphorylated and aggregated α-synuclein protein, as well as gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Parkinson's disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Parkinson's-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence α-synuclein neurotoxicity in aging adult brains. In proof of principle studies, we will validate a novel system for studying non-cell autonomous neurodegeneration in α-synucleinopathy. In addition, based on the observation that many genes implicated in Parkinson's disease through genome wide genetic association studies are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these genes in glia on α-synuclein induced neurotoxicity. These studies will develop a novel methodology for studying the effect of glia on the neurodegeneration associated with Parkinson's disease and will ultimately expand the array of molecular and cellular targets relevant for therapy development in this common and devastating disorder.

帕金森氏病是最常见的运动障碍，其临床特征是震颤和 运动迟缓，以及更广泛的疾病形式中的认知下降。经典 帕金森氏病的神经病理学特征包括神经元内路易体， 神经元内沉积异常磷酸化和聚集的α-突触核蛋白，以及 神经胶质增生神经胶质病理学通常被认为是继发性或反应性变化。但最近的 对正常和病理性神经胶质生物学的理解的进展反而表明，神经胶质可能发挥着 在神经系统疾病，包括帕金森氏病中发挥积极作用。在这里，我们采用遗传学方法， 定义介导神经胶质对帕金森氏症相关神经变性影响的蛋白质和途径。 利用先进的分子和遗传工具，短寿命和保守的神经胶质生物学 在果蝇中，我们将鉴定可以影响α-突触核蛋白神经毒性的神经胶质蛋白和途径， 老化的成年人大脑在原理研究的证明中，我们将验证一个用于研究非细胞的新系统。 α-突触核蛋白病的自主性神经变性此外，根据观察， 通过全基因组遗传关联研究， 主要或基本上在神经胶质细胞中，我们将测试上调和下调这些 α-synuclein诱导的神经毒性。这些研究将开发一种新的方法， 研究神经胶质对帕金森氏症相关神经退化的影响， 扩大了与治疗开发相关的分子和细胞靶点阵列， 毁灭性的混乱