Progranulin deficiency and microglia senescence in neurodegeneration

项目总结 神经胶质细胞的异常激活被认为促进了神经退行性变。但是，是什么触发了神经胶质细胞的激活 神经胶质细胞-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仍然存在 不清楚。这一提议的科学前提是基于之前发表的工作，即在 人类前颗粒蛋白(GRN)基因是额颞部痴呆(FTD)的主要致病因素。GRN基因突变导致 脑组织中前颗粒蛋白(PGRN)水平急剧下降，最终导致神经病理 以严重的胶质细胞增生，严重的神经元丢失和RNA结合蛋白TDP-43的聚集为特征 残留神经元(也称为“TDP-43蛋白病”)。除了它在FTD中的作用外，单核苷酸 GRN基因的多态性(SNP)与TDP-43蛋白病的风险增加有关 阿尔茨海默病(AD)和大脑老化。综上所述，这些结果支持了PGRN缺乏的观点 可能对神经退行性变有更广泛的影响。探讨前列腺素RN缺乏在糖尿病发病中的作用 神经退行性变，我们已经证明了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，导致强迫症 这些小鼠的紊乱(OCD)样行为。此外，我们使用了单细胞转录分析来显示 GRN-/-小胶质细胞表现出早期发病和持续的转录转录变化 内溶酶途径与先天免疫功能。此外，蛋白质组学和形态分析在中国 GRN-/-小胶质细胞表现出细胞衰老的显著特征，包括吞噬功能增强、溶酶体 功能障碍，增殖停滞，补体C1q和C3b分泌增加。这些结果支持 前列腺素RN缺乏扰乱内溶酶体功能并激活细胞衰老的假说 小胶质细胞内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细胞 死亡。为了验证这一假说，我们将(1)确定整合素αvβ3和转化生长因子-β途径在促进 Grn-/-小胶质细胞的细胞衰老，(2)Grn-/-衰老小胶质细胞的分泌表型 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和阿尔茨海默病中的衰老和神经变性。这项提案的结果将提供 前列腺素RN缺乏在小胶质细胞衰老中的机制及其作用的重要见解 FTD和AD的神经退行性变。

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.