# Interactions between progranulin insufficiency and TDP-43

> **NIH NIH F30** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $42,629

## Abstract

PROJECT SUMMARY
Frontotemporal Dementia (FTD) is a major cause of early onset dementia and patients can develop a wide range
of symptoms including behavioral changes and language impairments. Heterozygous mutations in the
progranulin gene (GRN) result in haploinsufficiency of the protein and cause FTD with TDP-43 pathology. TDP-
43 is a RNA binding protein that, in disease states, mislocalizes to the cytoplasm and forms insoluble inclusions.
All FTD-GRN patients develop TDP-43 pathology, however it is not understood how partial loss of progranulin
promotes TDP-43 mislocalization and aggregation. Progranulin heterozygous mice (Grn+/–) are the genetic
model of FTD-GRN and develop age dependent behavioral abnormalities, but do not develop TDP-43 pathology.
This project uses Grn+/– mice crossed with human TDP-43 transgenic mice (hTDP+) to investigate whether
progranulin insufficiency results in TDP-43 dysregulation. Initial studies of the Grn+/–:hTDP+ mice show a severe
impairment of social dominance behavior and an increase in insoluble TDP-43 in the medial prefrontal cortex
(mPFC), a region critical for normal social dominance behavior. Additionally, preliminary studies suggest that
there may be impairments in TDP-43-dependent splicing and autoregulation in the Grn+/–:hTDP+ mice. My
overarching hypothesis is that the synergistic effects of progranulin insufficiency and TDP-43 overexpression on
social dominance behaviors are due to TDP-43 dysregulation in the mPFC. This proposal will test two aims: 1)
Determine if progranulin insufficiency promotes TDP-43 mislocalization and dysregulation in the mPFC and 2)
Determine if impaired social dominance behaviors are driven by hTDP expression in the mPFC. As behavioral
changes are a major feature of FTD, determining the role of TDP-43 in the mPFC could be vital for developing
future therapeutics. The overall goal of the training plan is to instruct the PI in neurodegeneration research and
provide a solid foundation for a successful career as a physician scientist. A project based in translational
approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring
physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety
of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4)
present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct
research.

## Key facts

- **NIH application ID:** 10823777
- **Project number:** 1F30AG085889-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Anna K Cook
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,629
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823777

## Citation

> US National Institutes of Health, RePORTER application 10823777, Interactions between progranulin insufficiency and TDP-43 (1F30AG085889-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10823777. Licensed CC0.

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