# Molecular basis of VCP-linked degeneration

> **NIH NIH R00** · LOUISIANA STATE UNIV A&M COL BATON ROUGE · 2020 · $249,000

## Abstract

Valosin containing protein (VCP) is the causative gene for several degenerative diseases, including
frontotemporal dementia and ALS, but the molecular mechanisms underlying VCP diseases are unknown. To
investigate potential mechanisms of VCP-mediated cellular degeneration, we are using CRISPR knock-in
genome engineering to generate endogenous gene replacements of VCP disease mutations in Drosophila.
The major hallmark of VCP diseases is the abnormal accumulation of toxic protein aggregates in the
cytoplasm, hinting at a defect in protein clearance mechanisms. Recently, we and other labs have found that
several VCP disease mutations are linked to defects in autophagy-mediated degradation. We are now
investigating how VCP disease mutations disrupt autophagy-dependent protein clearance. In our initial studies,
we made a surprising discovery that lysosomes do not purely exist as vesicular structures, as they are
classically viewed, but form expansive tubular structures in multiple cell types, including muscles and glia.
These unique lysosomal organelles require VCP for their formation and/or maintenance, as over-expression of
several disease-causing VCP mutations collapse the tubular architecture of lysosomes and consequently
disrupt autophagosome-lysosome fusion. We hypothesize that disruption of lysosome tubules is a direct cause
of the autophagy defects observed in VCP-associated diseases. The broad objectives of this proposal are: (1)
to identify the molecular mechanisms by which VCP supports lysosome structure and function in normal,
healthy cells; and (2) to clarify how these functions are disrupted in disease states.

## Key facts

- **NIH application ID:** 9983836
- **Project number:** 5R00NS100988-04
- **Recipient organization:** LOUISIANA STATE UNIV A&M COL BATON ROUGE
- **Principal Investigator:** Alyssa Johnson
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983836

## Citation

> US National Institutes of Health, RePORTER application 9983836, Molecular basis of VCP-linked degeneration (5R00NS100988-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983836. Licensed CC0.

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