# Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models

## TL;DR

This study shows that lacking progranulin does not worsen TDP-43-related brain issues in mice, but it does affect behavior and glial cells.

## Contribution

The study clarifies that PGRN deficiency does not worsen TDP-43 pathology in specific mouse models.

## Key findings

- PGRN deficiency causes mild glial activation and behavioral deficits in TDP-43Q331K mice.
- RNA-seq shows immune pathways are upregulated and myelination pathways are downregulated in PGRN-deficient mice.
- PGRN loss does not worsen TDP-43 pathology or motor deficits in human TDP-43 transgenic mice.

## Abstract

The progranulin (PGRN) protein is tightly linked with TDP-43 proteinopathy in neurodegenerative diseases. However, how PGRN regulates TDP-43 proteinopathy remains unclear. In this study, we investigated the effect of PGRN loss on TDP-43 pathology in the TDP-43Q331K knock-in mice expressing an ALS-linked TDP-43 mutation at the endogenous level, and in the transgenic mice overexpressing human TDP-43 in neurons. We found that PGRN deficiency leads to mild glial activation and behavioral deficits in TDP-43Q331K mice without inducing typical TDP-43 pathology. RNA-seq analysis reveals upregulation of immune pathways and downregulation of myelination-related pathways in PGRN-deficient TDP-43Q331K mice. In addition, we observed myelination defects in human TDP-43 transgenic mice, but PGRN loss does not exacerbate TDP-43 pathology, myelination defects, and motor deficits in this mouse strain. Our studies demonstrated that PGRN deficiency exacerbates behavioral deficits and glial pathology caused by TDP-43 Q331K mutation but has minimal effect on TDP-43 pathology in mouse models.