Progranulin deficiency and microglia senescence in neurodegeneration

神经退行性变中颗粒体蛋白前体缺乏和小胶质细胞衰老

• 批准号: 10044228
• 负责人: Eric J Huang
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10044228
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amino Acids; Behavior; Cell Aging; Cells; Complement 1q; Complement 3b; Defect; Disease; Exhibits; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; GRN gene; Genes; Gliosis; Hippocampus (Brain); Homeostasis; Human; ITGB3 gene; Integrin alphaV; Integrin alphaVbeta3; Integrins; Knock-in Mouse; Knock-out; Lead; Link; Mediating; Microglia; Modeling; Molecular; Morphology; Mus; Mutation; Natural Immunity; Nerve Degeneration; Neuroglia; Neurons; Obsessive-Compulsive Disorder; PGRN gene; Pathology; Pathway interactions; Patients; Phagocytosis; Phenotype; Physiological; Property; Proteomics; Publishing; RNA-Binding Proteins; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Stable Isotope Labeling; TGF Beta Signaling Pathway; Testing; Thalamic structure; Toxic effect; Transforming Growth Factor beta; Up-Regulation; Vesicle; Work; aging brain; base; brain tissue; cell motility; early onset; glial activation; innovation; insight; mouse model; neuron loss; neuropathology; neurotoxicity; programs; protein TDP-43; senescence; synaptic pruning; therapeutic target; transcriptomics

PROJECT SUMMARY Aberrant glial activation has been postulated to promote neurodegeneration. But, what triggers glial activation and how perturbations to glia-neuron interaction contribute to brain aging and neurodegeneration remains unclear. The scientific premise of this proposal is based on previously published work that dominant mutation in human Progranulin (GRN) gene is a major cause for frontotemporal dementia (FTD). Mutations in GRN cause a drastic reduction in Progranulin (PGRN) protein levels in brain tissues and eventually lead to neuropathology characterized by profound gliosis, severe neuron loss, and aggregation of RNA binding protein TDP-43 in remaining neurons (also known as “TDP-43 proteinopathy”). In addition to its role in FTD, single nucleotide polymorphism (SNP) in the GRN gene has been associated with increased risk of TDP-43 proteinopathy in Alzheimer's disease (AD) and in the aging brain. Together, these results support the idea that PGRN deficiency may have broader impacts on neurodegeneration. To investigate the role of PGRN deficiency in neurodegeneration, we have shown that mouse models of PGRN deficiency recapitulate several key neuropathological features in FTD caused by GRN mutations, including microglial activation, microglia-mediated synaptic pruning, and dysfunction in the thalamocortical circuit, which contribute to obsessive-compulsive disorder (OCD)-like behaviors in these mice. In addition, we used single cell transcriptomic analyses to show that Grn-/- microglia exhibit early onset and persistent transcriptomic changes in genes involved in the endolysosomal pathway and innate immunity functions. Furthermore, proteomic and morphological analyses in Grn-/- microglia revealed prominent features of cellular senescence, including increased phagocytosis, lysosomal dysfunction, proliferative arrest, and increased secretion of complements C1q and C3b. These results support the hypothesis that PGRN deficiency disrupts endolysosomal function and activates the cellular senescence program in microglia leading to persistent microglial activation to promote synaptic pruning and neuronal cell death. To test this hypothesis, we will (1) determine the role of integrin αvβ3 and TGF-β pathway in promoting cellular senescence in Grn-/- microglia, (2) characterize the secretory phenotype in senescent microglia in Grn-/- mice and its impact on neurodegeneration, and (3) elucidate the impact of PGRN deficiency on microglial senescence and neurodegeneration in FTD and Alzheimer's disease. Results from this proposal will provide critical insights into the mechanism of PGRN deficiency in microglial senescence and its role in neurodegeneration in FTD and AD.

项目摘要 已经假定异常的神经胶质激活以促进神经退行性。但是，触发神经胶质激活的原因 以及胶质神经元相互作用的扰动如何导致脑衰老和神经退行性变化 不清楚。该提案的科学前提是基于先前发表的工作 人前植物（GRN）基因是额颞痴呆（FTD）的主要原因。 GRN中的突变导致 脑组织中易生蛋白（PGRN）蛋白水平的急剧降低，最终导致神经病理学 以深度神经胶质病，严重的神经元丧失和RNA结合蛋白TDP-43的聚集为特征 其余神经元（也称为“ TDP-43蛋白质病”）。除了其在FTD中的作用外，单核苷酸 GRN基因中的多态性（SNP）与TDP-43蛋白质病风险的增加有关 阿尔茨海默氏病（AD）和大脑衰老。这些结果共同支持了PGRN缺乏症的想法 可能对神经变性产生更广泛的影响。调查PGRN缺乏在 神经变性，我们已经表明，PGRN缺乏症的小鼠模型概括了几个关键 由GRN突变引起的FTD的神经病理特征，包括小胶质细胞激活，小胶质细胞介导 丘脑皮质回路中的突触修剪和功能障碍，这有助于强迫症 这些小鼠的疾病（OCD）类似行为。此外，我们使用单细胞转录组分析显示 GRN - / - 小胶质细胞暴露了早期发作和涉及的基因的持续转录组变化 内侧溶血途径和先天免疫学功能。此外，蛋白质组学和形态学分析 GRN - / - 小胶质细胞揭示了细胞感应的突出特征，包括吞噬作用增加，溶酶体 功能障碍，逮捕增殖以及C1Q和C3B完成的分泌增加。这些结果支持 PGRN缺乏症会破坏内溶性功能并激活细胞感应的假设 小胶质细胞的程序导致持续的小胶质细胞激活，以促进突触修剪和神经元细胞 死亡。为了检验该假设，我们将（1）确定整联蛋白αVβ3和TGF-β途径在促进中的作用 GRN - / - 小胶质细胞中的细胞感应，（2）表征GRN中的Senscent小胶质细胞中的秘密表型 - / - 小鼠及其对神经变性的影响，（3）阐明PGRN缺乏对小胶质细胞的影响 FTD和阿尔茨海默氏病的衰老和神经变性。该提议的结果将提供 对小胶质细胞感应中PGRN缺乏症机制的重要见解及其在 FTD和AD中的神经变性。