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Investigating the role of progranulin in TDP-43 proteinopathy

研究颗粒体蛋白前体在 TDP-43 蛋白病中的作用

基本信息

批准号：
10510687
负责人：
Fenghua Hu
金额：
$ 44.94万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510687
关键词：
Ablation Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Astrocytes Behavioral Brain Diseases Cognitive Complement Cre lox recombination system Defect Dependovirus Disease Encephalopathies Event Frontotemporal Lobar Degenerations GRN gene Homeostasis Huntington Disease Impaired cognition Lead Light Link Measures Mediating Microglia Modeling Molecular Motor Mus Mutation Myelin Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear PGRN gene Pathologic Pathology Pathway interactions Phenotype Phosphorylation Physiological Post-Translational Protein Processing Proteins RNA RNA Splicing RNA-Binding Proteins Research Role Signal Transduction Ubiquitination Work age related cellular pathology frontotemporal lobar dementia-amyotrophic lateral sclerosis granulin insight invention molecular pathology motor deficit mouse model mutant neuroinflammation new therapeutic target novel overexpression protein TDP-43 protein function proteostasis therapeutic development

项目摘要

Investigating the role of progranulin in TDP-43 proteinopathy is a common signature shared by many neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Mutations in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, are a main cause of FTLD with TDP- 43 aggregates. However, molecular pathways leading to TDP-43 proteinopathy are still not clear. In this proposal, we aim to determine the role of PGRN in TDP-43 proteinopathy using a recently characterized TDP- 43 mouse model expressing ALS-associated TDP-43 mutant (Q331K) at endogenous levels. In Aim1, we will determine the effect of PGRN on TDP-43 protein homeostasis and TDP-43 function in both PGRN deficient and overexpressing conditions. In Aim2, we will examine the behavioral and pathological changes of TDP- 43Q331K mice with PGRN deleted or overexpressed. In Aim 3, we will investigate the role of microglial versus neuronal PGRN in TDP-43 proteinopathy by deleting PGRN specifically in microglia vs neurons. In addition, we will dissect how secreted factors from PGRN deficient microglia trigger TDP-43 aggregation in neurons and determine how neuronal PGRN functions to regulate TDP-43 protein homeostasis. The proposed studies will shed light on not only the mechanisms involved in TDP-43 proteinopathy but also the physiological functions of PGRN. Our work will also facilitate therapeutic development for ALS/FTLD, AD, and other devastating neurodegenerative diseases with TDP-43 proteinopathy and/or PGRN deficiency.

研究蛋白前蛋白在TDP-43蛋白病变中的作用是许多神经退行性疾病的共同特征，包括阿尔茨海默病（AD）和额颞叶变性（FTLD）。颗粒蛋白（GRN）基因突变导致颗粒蛋白前（PGRN）蛋白单倍不足，是TDP- 43聚集的FTLD的主要原因。然而，导致TDP-43蛋白病变的分子途径尚不清楚。在这项提议中，我们的目标是确定PGRN在TDP-43蛋白病变中的作用，使用最近表征的内源性表达als相关TDP-43突变体（Q331K）的TDP-43小鼠模型。在Aim1中，我们将确定PGRN在PGRN缺乏和过表达条件下对TDP-43蛋白稳态和TDP-43功能的影响。在Aim2中，我们将检测PGRN缺失或过表达的TDP- 43Q331K小鼠的行为和病理变化。在Aim 3中，我们将通过在小胶质细胞和神经元中特异性地删除PGRN来研究小胶质细胞和神经元PGRN在TDP-43蛋白病变中的作用。此外，我们将剖析PGRN缺陷小胶质细胞分泌因子如何触发神经元中TDP-43的聚集，并确定神经元PGRN如何调节TDP-43蛋白的稳态。这些研究不仅将揭示TDP-43蛋白病变的机制，还将揭示PGRN的生理功能。我们的工作也将促进ALS/FTLD， AD和其他具有TDP-43蛋白病变和/或PGRN缺乏的破坏性神经退行性疾病的治疗开发。