Mechanisms of mutanthuntingtin aggregate engulfment and spreading by phagocytic glia

吞噬细胞胶质细胞吞噬和扩散突变亨廷顿蛋白聚集体的机制

基本信息

批准号：
10514794
负责人：
Margaret Panning Pearce
金额：
$ 9.3万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10514794
关键词：
Address Adult Age Alzheimer&apos s Disease Anatomy Appearance Astrocytes Axon Biological Biology Brain Brain region Cell Culture Techniques Cells Cessation of life Complex Cultured Cells Cytoplasm Data Defect Disease Drosophila genus Environment Equilibrium Functional disorder Generations Genes Genetic Screening Goals Growth Homologous Gene Huntington Disease Huntington gene Huntington protein In Vitro Incidence Interneurons Lesion Mammalian Cell Measures Mediating Membrane Modeling Molecular Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurons Neuropathogenesis Olfactory Pathways Orthologous Gene Outcomes Research Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pattern Phagocytes Phagocytosis Phagosomes Prions Property Proteins Public Health Publishing RNA Interference Reporting Research Research Support Role SNAP receptor Supervision Synapses System Testing Time Toxic effect Work age related neurodegeneration alpha synuclein base cell type defined contribution fly frontotemporal lobar dementia-amyotrophic lateral sclerosis graduate student in vivo insight misfolded protein monolayer mutant nerve injury nervous system disorder neuron loss neuropathology neuroprotection neurotoxic new therapeutic target novel postsynaptic neurons presynaptic prion-like protein aggregation protein misfolding response response to injury scavenger receptor spatiotemporal tau Proteins therapeutic target therapeutically effective transmission process undergraduate student

项目摘要

PROJECT SUMMARY Neurodegenerative diseases are characterized by the progressive appearance of insoluble inclusions that arise due to protein misfolding in the brain. Much research has focused on determining mechanisms by which these protein lesions cause dysfunction and loss of neurons and glia. Accumulating evidence supports the hypothesis that protein assemblies associated with most neurodegenerative diseases propagate in the brain by templating the aggregation of properly-folded versions of the same protein, similarly to infectious prions. However, it is still not well understood how “prion-like” aggregates spread between different cell types in the brain or the relevance of this to neuropathogenesis. The long-term goal of our research is to identify mechanisms underlying protein aggregate-induced toxicity and spreading between neurons and glia in the degenerating brain. The overall objective of this project is to determine normal and pathological functions of phagocytic glia in response to formation of mutant huntingtin (mHTT) aggregates in neurons. Prior research showing that glial responses to neural injury shift from beneficial to harmful over time, and emerging evidence that phagocytic glia participate in aggregate clearance and spreading provide rationale for the current project. The central hypothesis is that incomplete clearance of engulfed neuronal mHTT aggregates by phagocytic glia promotes formation and growth of a reservoir of seeding-competent, prion-like species in the brain. This hypothesis was formulated based on findings that glia mediate prion-like transfer of mHTT, tau, and a-synuclein aggregates, and that phagocytic clearance of engulfed debris becomes less effective with age and in the disease state. Our recent work indicates that prion-like transfer of mHTT aggregates between synaptically-connected neurons requires Draper-dependent phagocytosis, an evolutionarily-conserved glial pathway for clearing debris in the brain. The central hypothesis will be tested in three Specific Aims, carried out in complementary in vivo Drosophila and in vitro mammalian cell culture models. In Aim 1, effects of neuronal mHTT aggregates on glial responses to neural injury will be measured in adult fly brains to gain insight into whether mHTT aggregate engulfment leads to glial dysfunction. In Aim 2, RNAi-based forward genetic screens will identify modifiers of prion-like spreading of engulfed neuronal mHTT aggregates to the glial cytoplasm. In Aim 3, roles of the mammalian Draper homolog MEGF10 in mHTT aggregate transfer between co-cultured neuronal and astrocytic cells will be determined. These studies will identify novel mechanisms about the basic biology underlying phagocytosis, and disease-related mechanisms that drive protein aggregate-induced neurodegeneration in multiple cell types. The proposed research is significant because it addresses critical questions of how phagocytic glia interact with neurons to drive pathogenesis in potentially many neurological disorders. Our findings will reveal new information about aggregate-related pathogenesis underlying neurodegeneration and have great potential to identify targets for novel therapies that treat the underlying cause of these fatal disorders.

项目摘要神经退行性疾病的特征是出现的不溶性包裹物的逐渐出现由于蛋白质在大脑中的折叠错误。许多研究重点是确定这些机制蛋白质病变会导致神经元和神经胶质的功能障碍和丧失。积累的证据支持假设与大多数神经退行性疾病相关的蛋白质组件通过模板在大脑中传播适当折叠版本的同一蛋白质的聚集，类似于感染性prions。但是，仍然是不太了解“类似prion”的聚集体如何在大脑中的不同细胞类型之间传播或相关性这是神经病发生的。我们研究的长期目标是识别蛋白质的基础机制骨料引起的毒性和神经元和神经胶质在退化的大脑中的扩散。总体该项目的目的是确定吞噬胶质神经胶质的正常和病理功能神经元中突变亨廷汀（MHTT）聚集体的形成。先前的研究表明，神经胶质反应神经损伤随着时间的推移从有益变为有害的转变，以及吞噬细胞胶质参与的新兴证据汇总间隙和扩散为当前项目提供了基本原理。中心假设是吞噬胶质细胞的吞噬神经元MHTT骨料的清除不完整可促进形成和生长大脑中具有播种，类似prion的种子样物种的水库。该假设是根据 GliA介导MHTT，TAU和A-核蛋白聚集体的Prion样转移的发现，该吞噬细胞随着年龄和疾病状态，吞噬碎片的清除效率降低。我们最近的工作表明在合成连接神经元之间MHTT聚集体的prion样转移需要依赖性draper 吞噬作用，一种用于清除大脑碎屑的胶质途径。中心假设将以三个特定目标进行测试，在体内果蝇和体外哺乳动物细胞中进行。文化模型。在AIM 1中，神经元MHTT聚集体对神经元损伤的神经胶质反应的影响将是在成年苍蝇大脑中测量，以深入了解MHTT骨料吞噬是否导致神经胶质功能障碍。在AIM 2中，基于RNAi的正向遗传筛选将识别吞噬神经元的prion样传播的修饰符 MHTT聚集到神经胶质细胞质。在AIM 3中，MHTT的哺乳动物Draper同源物MEGF10的角色将确定共培养神经元和星形细胞细胞之间的聚集转移。这些研究会确定有关基本生物学基础吞噬作用以及与疾病相关机制的新型机制该驱动蛋白质骨料诱导的多种细胞类型中的神经退行性。拟议的研究是重要的是因为它解决了吞噬细胞胶质与神经元如何驱动的关键问题潜在的许多神经系统疾病的发病机理。我们的发现将揭示有关的新信息与神经退行性的基本发病机理相关的发病机理具有巨大的潜力，可以识别靶标治疗这些致命疾病的根本原因的新型疗法。