# Investigating the impact of p97 mutation in Amyotrophic Lateral Sclerosis

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2022 · $247,500

## Abstract

Protein homeostasis decline is a significant contributor to the development of Amyotrophic Lateral Sclerosis
(ALS) and other neurodegenerative disorders. With an ever-expanding aging population and no reliable
therapies, these devastating diseases will place a significant burden on health care in the coming decades.
 The p97 AAA-ATPase is a ubiquitin-selective unfoldase that has critical roles in protein quality control.
Dedicated adaptor proteins target p97 to ubiquitylated substrates and thereby impart specificity to this abundant
enzyme. Mutations in p97 cause familial ALS and are reported to impede p97 association with certain adaptors
and impair ER and mitochondria associated quality control suggesting inadequate targeting to these organelles.
However, the impact of p97 mutation on its interactome and ubiquitylated substrates has not been studied
systematically in cell types impacted in disease, namely motor neurons and skeletal muscle.
 Here, we will establish an induced pluripotent stem cell (iPSC)-based model of motor neuron disease caused
by distinct p97 mutations. We will use this system to: (1) Investigate how mutant p97 remodels the motor neuron
and skeletal muscle proteome and physiology. Ubiquitylated substrates of p97 will be identified using quantitative
proteomics in each cell type. (2) Examine the impact of p97 mutation on known protein quality control pathways
in motor neurons skeletal muscle cells.
 Our studies will provide the first model of ALS caused by p97 mutation and will provide mechanistic insight
into how p97 mutation causes motor neuron and/or skeletal muscle demise. We anticipate our cell-based model
may be used in the future for small molecule screens to identify lead molecules for therapy development. Given
the prevalence of p97 mutation, we anticipate these studies will have broad relevance to other in
neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10449848
- **Project number:** 1R21NS123631-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Malavika Raman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $247,500
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449848

## Citation

> US National Institutes of Health, RePORTER application 10449848, Investigating the impact of p97 mutation in Amyotrophic Lateral Sclerosis (1R21NS123631-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10449848. Licensed CC0.

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