# Investigating the role of progranulin in TDP-43 proteinopathy

> **NIH NIH R21** · CORNELL UNIVERSITY · 2022 · $449,419

## Abstract

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.

## Key facts

- **NIH application ID:** 10510687
- **Project number:** 1R21AG078741-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Fenghua Hu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $449,419
- **Award type:** 1
- **Project period:** 2022-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510687

## Citation

> US National Institutes of Health, RePORTER application 10510687, Investigating the role of progranulin in TDP-43 proteinopathy (1R21AG078741-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10510687. Licensed CC0.

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