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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

基本信息

批准号：
10681318
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
项目类别：
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/10681318
关键词：
Alzheimer&apos s Disease Alzheimer&apos 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 Homeostasis Human ITGB3 gene Integrin alphaV Integrin alphaVbeta3 Integrins Knock-in Mouse Knock-out Knockout Mice 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 brain tissue cell motility dominant genetic mutation early onset glial activation innovation insight mouse model neuron loss neuropathology neurotoxicity programs protein TDP-43 senescence synaptic pruning therapeutic target transcriptomics

项目摘要

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.

项目摘要神经胶质细胞的异常活化被认为是促进神经退行性变的原因。但是，是什么触发了神经胶质的激活呢以及神经胶质-神经元相互作用的扰动如何导致大脑老化和神经退行性变，不清楚这一建议的科学前提是基于先前发表的工作，即显性突变，人颗粒蛋白前体（GRN）基因是导致额颞叶痴呆（FTD）主要原因。GRN的突变会导致脑组织中颗粒蛋白前体（PGRN）蛋白水平急剧降低，并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在神经元中的聚集。剩余神经元（也称为“TDP-43蛋白质病”）。除了在FTD中的作用外，单核苷酸 GRN基因中的SNP与TDP-43蛋白质病的风险增加相关，老年痴呆症（AD）和大脑老化。总之，这些结果支持PGRN缺乏的想法，可能对神经退化有更广泛的影响。研究PGRN缺陷在我们已经证明PGRN缺乏的小鼠模型概括了几个关键点， GRN突变引起的FTD的神经病理学特征，包括小胶质细胞活化、小胶质细胞介导的突触修剪和丘脑皮层回路功能障碍，这有助于强迫症强迫症（OCD）样行为。此外，我们使用单细胞转录组学分析来显示 Grn-/-小胶质细胞表现出早期发病和持续的转录组学变化的基因参与了内溶酶体途径和天然免疫功能。此外，蛋白质组学和形态学分析， Grn-/-小胶质细胞显示出细胞衰老的突出特征，包括吞噬作用增加、溶酶体功能障碍、增殖停滞和补体C1 q和C3 b分泌增加。这些结果支持 PGRN缺乏破坏内溶酶体功能并激活细胞衰老的假设在小胶质细胞中的程序导致持续的小胶质细胞活化，以促进突触修剪和神经元细胞死亡为了验证这一假设，我们将（1）确定整合素αvβ3和TGF-β途径在促进细胞凋亡中的作用。 Grn-/-小胶质细胞的细胞衰老，（2）表征Grn-/-小胶质细胞衰老的分泌表型。小鼠及其对神经退行性变的影响，和（3）阐明PGRN缺乏对小胶质细胞的影响， FTD和阿尔茨海默病中的衰老和神经变性。该提案的结果将提供对PGRN缺陷在小胶质细胞衰老中的机制及其在 FTD和AD中的神经变性。