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.

项目概要 异常的神经胶质激活被认为会促进神经退行性变，但是，是什么触发了神经胶质激活。 神经胶质细胞与神经元相互作用的扰动如何导致大脑衰老和神经退行性变仍然存在 尚不清楚该提议的科学前提是基于先前发表的显性突变的工作。 人类颗粒体蛋白前体 (GRN) 基因是导致额颞叶痴呆 (FTD) 的主要原因。 脑组织中颗粒体蛋白前体 (PGRN) 蛋白水平急剧下降，最终导致神经病理学 其特征是严重的神经胶质增生、严重的神经元丢失以及 RNA 结合蛋白 TDP-43 的聚集 剩余神经元（也称为“TDP-43 蛋白病”）除了在 FTD 中的作用外，单核苷酸。 GRN 基因中的多态性 (SNP) 与 TDP-43 蛋白病风险增加相关 阿尔茨海默病 (AD) 和衰老的大脑一起，这些结果支持了 PGRN 缺乏的观点。 可能对神经退行性疾病产生更广泛的影响。 神经退行性疾病，我们已经证明 PGRN 缺乏的小鼠模型概括了几个关键 GRN 突变引起的 FTD 的神经病理学特征，包括小胶质细胞激活、小胶质细胞介导的 突触修剪和丘脑皮质回路功能障碍，这些都会导致强迫症 此外，我们使用单细胞转录组分析来显示这些小鼠的类似强迫症（OCD）行为。 Grn-/-小胶质细胞在参与的基因中表现出早期发生和持续的转录组变化 此外，内溶酶体途径和先天免疫功能的蛋白质组学和形态学分析。 Grn-/-小胶质细胞揭示了细胞衰老的显着特征，包括吞噬作用增加、溶酶体 功能障碍、增殖停滞以及补体 C1q 和 C3b 的分泌增加这些结果支持。 PGRN 缺乏会破坏内溶酶体功能并激活细胞衰老的假设 小胶质细胞中的程序导致小胶质细胞持续激活，以促进突触修剪和神经元细胞 为了检验这一假设，我们将 (1) 确定整合素 αvβ3 和 TGF-β 途径在促进死亡中的作用。 Grn-/- 小胶质细胞中的细胞衰老，(2) 表征 Grn-/- 中衰老小胶质细胞的分泌表型 小鼠及其对神经退行性变的影响，以及（3）阐明 PGRN 缺乏对小胶质细胞的影响 该提案将提供 FTD 和阿尔茨海默病中的衰老和神经变性的结果。 对小胶质细胞衰老中 PGRN 缺乏机制及其作用的重要见解 FTD 和 AD 中的神经退行性疾病。