# Loss of VCP Function in Frontotemporal Lobar Degeneration

> **NIH NIH RF1** · UNIVERSITY OF PENNSYLVANIA · 2022 · $2,356,099

## Abstract

Rare genetic causes of human disease have the potential to reveal mechanistic insights into more
common sporadic disease. Tauopathies are a group of fatal neurologic diseases, including Alzheimer's disease,
where dementia and neurodegeneration are the result of accumulation of pathologic tau protein aggregates in
the form of neurofibrillary tangles, Pick bodies, or glial inclusions. We have identified a novel autosomal
dominant form of frontotemporal dementia with tau inclusions associated with a novel hypomorphic genetic
mutation in VCP which may be linked to a loss of anti-tau disaggregase activity. However, hypermorphic VCP
mutations cause a distinct disease called multisystem proteinopathy which can manifest as frontotemporal
lobar degeneration with TDP-43 inclusions. We propose three specific aims to understand the basic molecular
mechanisms by which this gene mutation leads to diverse pathologies. We will perform structural biology
studies to better understand how VCP protein interacts with pathologic protein aggregates, and how VCP
mutations affect disaggregase activity. We will extend these studies into cellular/neuronal VCP knock-in
models to determine how VCP mutations affect cellular VCP activity within a cellular context. Finally, we will
determine whether gains or losses of VCP activity can modify tau toxicity in vivo. Together, these mechanistic
studies will elucidate basic mechanisms by which VCP dysfunction leads to different types of proteinopathy,
providing the basis for future novel anti-tau therapies based on modulating VCP activity.

## Key facts

- **NIH application ID:** 10440933
- **Project number:** 1RF1AG065341-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Edward Byung-Ha Lee
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,356,099
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440933

## Citation

> US National Institutes of Health, RePORTER application 10440933, Loss of VCP Function in Frontotemporal Lobar Degeneration (1RF1AG065341-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440933. Licensed CC0.

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