# Progranulin deficiency and microglia senescence in neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $403,750

## Abstract

PROJECT SUMMARY
 Aberrant glial activation has been postulated to promote neurodegeneration. But, what triggers glial activation
and how perturbations to glia-neuron interaction contribute to brain aging and neurodegeneration remains
unclear. The scientific premise of this proposal is based on previously published work that dominant mutation in
human Progranulin (GRN) gene is a major cause for frontotemporal dementia (FTD). Mutations in GRN cause a
drastic reduction in Progranulin (PGRN) protein levels in brain tissues and eventually lead to neuropathology
characterized by profound gliosis, severe neuron loss, and aggregation of RNA binding protein TDP-43 in
remaining neurons (also known as “TDP-43 proteinopathy”). In addition to its role in FTD, single nucleotide
polymorphism (SNP) in the GRN gene has been associated with increased risk of TDP-43 proteinopathy in
Alzheimer's disease (AD) and in the aging brain. Together, these results support the idea that PGRN deficiency
may have broader impacts on neurodegeneration. To investigate the role of PGRN deficiency in
neurodegeneration, we have shown that mouse models of PGRN deficiency recapitulate several key
neuropathological features in FTD caused by GRN mutations, including microglial activation, microglia-mediated
synaptic pruning, and dysfunction in the thalamocortical circuit, which contribute to obsessive-compulsive
disorder (OCD)-like behaviors in these mice. In addition, we used single cell transcriptomic analyses to show
that Grn-/- microglia exhibit early onset and persistent transcriptomic changes in genes involved in the
endolysosomal pathway and innate immunity functions. Furthermore, proteomic and morphological analyses in
Grn-/- microglia revealed prominent features of cellular senescence, including increased phagocytosis, lysosomal
dysfunction, proliferative arrest, and increased secretion of complements C1q and C3b. These results support
the hypothesis that PGRN deficiency disrupts endolysosomal function and activates the cellular senescence
program in microglia leading to persistent microglial activation to promote synaptic pruning and neuronal cell
death. To test this hypothesis, we will (1) determine the role of integrin αvβ3 and TGF-β pathway in promoting
cellular senescence in Grn-/- microglia, (2) characterize the secretory phenotype in senescent microglia in Grn-/-
mice and its impact on neurodegeneration, and (3) elucidate the impact of PGRN deficiency on microglial
senescence and neurodegeneration in FTD and Alzheimer's disease. Results from this proposal will provide
critical insights into the mechanism of PGRN deficiency in microglial senescence and its role in
neurodegeneration in FTD and AD.

## Key facts

- **NIH application ID:** 10886015
- **Project number:** 5R01AG068290-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886015

## Citation

> US National Institutes of Health, RePORTER application 10886015, Progranulin deficiency and microglia senescence in neurodegeneration (5R01AG068290-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10886015. Licensed CC0.

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