# Elucidating the roles of protein disaggregases and developing enhanced diaggregases to counter diverse protein-misfolding disorders

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2024 · $594,657

## Abstract

PROJECT SUMMARY
The proper folding of proteins is essential for all life, making aberrant protein folding severely problematic. The
protein homeostasis (proteostasis) network is a tightly regulated system that ensures that proteins are folded
and degraded as necessary. However, misfolded proteins can overwhelm proteostasis. Misfolding is associated
with numerous devastating neurodegenerative, heart, and kidney disorders, as well as forms of cancer. Protein
disaggregases can engage misfolded substrates and dissolve them, promoting their return to proper fold and
function. Disaggregases may serve as the final defense against collapse of proteostasis. Our central hypothesis
is that disaggregases play key roles in maintaining cellular health, but are vulnerable when the proteostasis
network becomes overwhelmed in disease. Therefore, technologies that enhance disaggregase activity may be
therapeutically useful. However, disaggregases are the least characterized branch of the proteostasis network.
My research program focuses on advancing our understanding of how disaggregases counter misfolding, both
in health and under stress. We seek to elucidate how cells maintain proteostasis, how proteostasis fails, and
how protein disaggregases might ultimately be applied to prevent or reverse collapse of proteostasis. During the
first period of this award, we focused on engineering tailored Hsp104 variants, better understanding mechanisms
of misfolding, and have begun characterizing human disaggregases. During the next phase, we will continue
and expand our efforts to better understand the roles disaggregases play in safeguarding against misfolding. We
will focus on two primary themes: (1) we will develop finely-tuned Hsp104 variants and use these variants as
probes to test the effects of disaggregation in different systems. These studies will also reveal insights into the
mechanism of Hsp104, and we aim to better understand how Hsp104 recognizes and distinguishes among
substrates. Further, because Hsp104 is a member of the AAA+ family of proteins, which serve crucial roles
across biology, our findings can be broadly applied. (2) We will characterize and develop approaches to modulate
human disaggregases. Here, we will focus on understanding the structure, mechanism, and substrate repertoire
of human disaggregases. We also aim to develop approaches to modulate the activity of human disaggregases.
Beyond their possible therapeutic utility, finely-tuned disaggregases can be used as probes to test the hypothesis
that misfolded species are toxic, and that restoration of proteins to their native folds and functions can reverse
disease phenotypes. Ultimately we aim to apply the findings from these studies to develop new strategies to
treat protein-misfolding diseases. This is especially important because, despite intense efforts, there are no
effective therapeutics available to treat numerous protein-misfolding disorders.

## Key facts

- **NIH application ID:** 10841875
- **Project number:** 1R35GM153303-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Meredith E. Jackrel
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,657
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841875

## Citation

> US National Institutes of Health, RePORTER application 10841875, Elucidating the roles of protein disaggregases and developing enhanced diaggregases to counter diverse protein-misfolding disorders (1R35GM153303-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841875. Licensed CC0.

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