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，在临床上以震颤和 Bradykinesia以及该疾病的宽度形式的认知能力下降。经典的 帕金森氏病的神经病理学特征包括由神经内神经元内的身体形成 绝对磷酸化和聚集的α-突触核蛋白蛋白的神经元沉积以及 神经胶质病。神经胶质病理通常被认为是次要或反应性变化。但是，最近 理解正常和病理神经胶质生物学的进步已经表明，神经胶质可能发挥作用 在包括帕金森氏病在内的神经系统疾病中发挥了积极作用。在这里，我们采用一种遗传方法 定义蛋白质和途径，介导了神经胶质对帕金森相关的神经变性的影响。 利用高级分子和遗传工具，寿命短，并配置了神经胶质生物学 在果蝇中，我们将确定可以影响α-突触核蛋白神经毒性中的神经胶质蛋白和途径 成年大脑老化。在原则研究的证明中，我们将验证一种用于研究非细胞的新系统 α-突触核疾病中的自主神经变性。另外，基于观察到许多 通过基因组广泛的遗传关联研究在帕金森氏病中实施的基因被表达 我们将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的效果 在α-突触核蛋白诱导神经毒性上的神经胶质基因。这些研究将开发出一种新颖的方法论 研究神经胶质对与帕金森氏病相关的神经变性的影响，并最终将 扩展与这种常见和 毁灭性疾病。