Investigating the role of progranulin in TDP-43 proteinopathy

研究颗粒蛋白前体在TDP-43蛋白质病中的作用是许多神经退行性疾病共有的共同特征，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体（PGRN）蛋白单倍不足，是导致SDP- 43聚集体FTLD的主要原因。然而，导致TDP-43蛋白质病的分子途径仍然不清楚。在这个提议中，我们的目的是确定PGRN在TDP-43蛋白质病中的作用，使用最近表征的TDP- 43小鼠模型，在内源性水平表达ALS相关的TDP-43突变体（Q331 K）。在Aim 1中，我们将确定PGRN在PGRN缺陷和过表达条件下对TDP-43蛋白稳态和TDP-43功能的影响。在Aim 2中，我们将检查具有PGRN缺失或过表达的TDP-43 Q331 K小鼠的行为和病理变化。在目的3中，我们将通过特异性地在小胶质细胞与神经元中缺失PGRN来研究小胶质细胞与神经元PGRN在TDP-43蛋白质病中的作用。此外，我们将剖析PGRN缺陷的小胶质细胞分泌的因子如何触发TDP-43在神经元中的聚集，并确定神经元PGRN如何发挥作用来调节TDP-43蛋白的稳态。这些研究不仅有助于阐明TDP-43蛋白质病的发病机制，而且有助于阐明PGRN的生理功能。我们的工作还将促进ALS/FTLD，AD和其他具有TDP-43蛋白质病和/或PGRN缺乏的破坏性神经退行性疾病的治疗开发。

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.