# Dysregulation of p97/VCP disease mutants in IBM and FTLD-U

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $71,654

## Abstract

Project Summary
Many neurodegenerative diseases are thought to be caused by a buildup of toxic proteins in the brain from or
resulting in promotion of apoptosis. p97 AAA ATPase (also known as VCP, CDC48, TER ATPase) functions in
multiple biological processes, targeting proteins to 2 major degradation systems, the proteasome and
autophagy machinery. The key role of p97 in proteasome and autophagy degradations underscores its
importance and supports involvement of p97 dysregulation in protein misfolding, aggregation, and processing
errors, eventually resulting in cell death. Single amino acid mutations in p97/VCP cause autosomal dominant
human disorders including hereditary frontotemporal dementia hereditary (FTD) and a specific condition called
inclusion body myopathy with Paget disease of the bone plus ALS, a motor neuron disease also known as Lou
Gehrig's disease. Mutation sources could be genetic, environmental, spontaneous, or age related. The goal of
this project is to identify key pathogenic mechanisms that will be used to develop precision therapy to correct
the defect due to p97 disease mutations, without damaging normal p97 functions. Our central hypothesis: p97
disease mutants have abnormal conformation, which in turn leads to altered protein interactome that in specific
cells including neuronal cells cause pathogenic effect To test this hypothesis and to identify key pathogenic
mechanisms that can act as targets for therapeutic intervention, we propose to compare the interactome of WT
and disease mutants of p97 in neuronal and muscle cells derived from patient fibroblasts and then use genetic
and biochemical approaches to determine the effect of the altered interactors in regulating p97 ATPase activity
and in modulating the disease phenotype. Overall, a new paradigm of how to develop mutant-targeted
therapeutics for neurodegenerative diseases—especially for causative mutants in the ATPase protein family—
will be established.

## Key facts

- **NIH application ID:** 10166541
- **Project number:** 3R01NS102279-04S1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Tsui-Fen Chou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,654
- **Award type:** 3
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166541

## Citation

> US National Institutes of Health, RePORTER application 10166541, Dysregulation of p97/VCP disease mutants in IBM and FTLD-U (3R01NS102279-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166541. Licensed CC0.

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