# Chemical Control of Misfolded Protein Fate

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $1,422,000

## Abstract

7. Project Summary
The accumulation of misfolded proteins concurrent with disease progression is a hallmark of
degenerative disorders known collectively as proteinopathies. These include dementias such as
Alzheimer’s, Parkinson’s and Huntington’s Disease among many others, as well as systemic
amyloidosis disorders. However, if and how aggregated species contribute to disease etiology
and progression remains poorly understood. Over the past 100 years, there has been significant
advancement in understanding the pathological signatures and risk factors of proteinopathies but
the molecular mechanisms of disease have remained elusive. In this application, I propose the
development of new chemical tools for selectively manipulating aggregate proteostasis in cells
and in vivo using a targeted protein degradation approach. To demonstrate feasibility, this
approach was previously applied to investigate misfolded tau, leading to new insights into tau as
a mediator of cell stress vulnerability in frontotemporal dementia neurons. Several strategies are
presented to improve the throughput, scope, and utility of this approach across proteinopathies,
as well as future applications.
The major innovation of the proposed research is to take technologies and concepts learned from
the field of targeted protein degradation (TPD) for cancer therapy, which has been an
exceptionally active and successful area of research over the past 5 years, and apply them to
central challenges in neurodegenerative diseases, where TPD has yet to be applied broadly. I
believe this approach has high potential to yield significant advancement in both our
understanding of the molecular mechanisms underlying neurodegenerative diseases and in
identifying new therapeutic strategies to treat them.

## Key facts

- **NIH application ID:** 10473133
- **Project number:** 1DP2NS132610-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Fleur Marcia Ferguson
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,422,000
- **Award type:** 1
- **Project period:** 2022-09-28 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473133

## Citation

> US National Institutes of Health, RePORTER application 10473133, Chemical Control of Misfolded Protein Fate (1DP2NS132610-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10473133. Licensed CC0.

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