# Protein aggregation in inclusion body and myofibrillar myopathies

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $646,536

## Abstract

The overarching goal of this R01 is to explore the hypothesis that a prion-like mechanism of
proteopathic spread occurs in inclusion body myopathy (IBM). IBM patient muscle has two
distinct pathologies, 1) protein inclusions containing aggregated proteins such as TDP-43 and
desmin and 2) rimmed vacuoles consisting of autophagosomes, lysosomes and endosomes.
How these two pathologies are pathomechanistically connected is unclear. We suggest that
aggregated proteins such as TDP-43 and desmin enter the endolysosomal system damaging
the membrane leading to a failure in lysosomal degradation and signaling pathways resulting in
muscle degeneration. Our aims will test 1) confirm that muscle derived TDP-43 proteopathic
seeds can induce TDP-43 aggregation in recipient myofibers. 2) Demonstrate that proteopathic
seeds can induce lysosomal membrane permeabilization resulting in autophagic and lysosomal
dysfunction 3) Evaluate myofiber to myofiber propagation of proteopathic aggregates. Upon
completion of these aims, we will have defined a unique mechanism of IBM pathogenesis and
identified a novel point of therapeutic intervention by blocking the spread of protein aggregates.

## Key facts

- **NIH application ID:** 10882761
- **Project number:** 2R01AG031867-16
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** CONRAD C WEIHL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $646,536
- **Award type:** 2
- **Project period:** 2009-01-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882761

## Citation

> US National Institutes of Health, RePORTER application 10882761, Protein aggregation in inclusion body and myofibrillar myopathies (2R01AG031867-16). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10882761. Licensed CC0.

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