权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/10044228
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain 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 (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

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.

项目总结