Investigating the role of progranulin in TDP-43 proteinopathy

研究原颗粒在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)基因突变导致原颗粒蛋白(PGRN)蛋白单倍性不足是导致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仍不清楚。在这项建议中，我们的目标是利用最近确定的在内源性水平表达ALS相关TDP-43突变体(Q331K)的TDP-43小鼠模型来确定PGRN在TDP-43蛋白病变中的作用。在AIM1中，我们将确定在PGRN缺乏和过表达的情况下，PGRN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。在目标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，我们还将剖析PGRN缺陷的小胶质细胞分泌的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蛋白的动态平衡。这些研究不仅有助于阐明TDP-43蛋白病的发病机制，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蛋白病和/或PGRN缺乏症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.