# Mechanism of Aggregation and Disaggregation of Huntingtin

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Huntington's disease (HD) is a fatal neurodegenerative disorder affecting the physical, mental, and emotional
state of approximately 1 in 10,000 individuals. There is no cure or effective treatment for this disease, a factor
that stems directly from the lack of knowledge regarding the mechanism underlying this disorder. HD is caused
by a genetic mutation in the polyglutamine (polyQ) domain of Huntingtin exon 1 (Htt_ex1). This mutation
causes the polyQ tract to become pathologically expanded (>36Q), and for reasons that remain unknown, this
expansion alters the function of the protein and causes it to become toxic and prone to misfolding and
aggregation. In order to understand how a polyQ expansion leads to disease, I will utilize a combination of
spectroscopic techniques to identify and characterize the molecular features that are affected in huntingtin (Htt)
monomers and fibrils. Monomers and fibrils represent important conformers in the aggregation pathway and
are prominent sources of toxicity. Specifically, I aim to investigate how the C-terminal domain of these
conformers is affected by a polyQ expansion and whether this domain (C-terminus) facilitates the interaction of
Htt and the chaperone DnaJB1. Mounting evidence, including recent findings from our lab, has alluded to the
importance of this region in the overall organization of toxic Htt fibril species. Characterization of this region
may therefore hold the key to understanding the mechanism of Htt aggregation and reveal potential targets for
the disaggregation of fibrils. In aim 1, I will characterize the structure of mutant (>36Q) and wild type (<35Q)
monomers using solid-state Nuclear Magnetic Resonance (ssNMR) and an innovative sample preparation
method that allows for the trapping of Htt in its monomeric state. In doing so, I plan to uncover conformational
changes that contribute to the pathogenesis of HD. In aim 2, I will utilize ssNMR and Electron Paramagnetic
Resonance (EPR) to identify the sites that facilitate Htt fibril recognition by the chaperone DnaJB1.
Identification of such sites will be key in understanding the mechanism underlying aggregate identification and
disaggregation. Ultimately, my findings will allow for greater insight into the molecular features driving the
mechanism of protein misfolding, disaggregation, and toxicity in Huntington's disease, and thereby provide key
targets for the development of efficacious therapeutics.

## Key facts

- **NIH application ID:** 10018953
- **Project number:** 5F31NS105524-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Silvia Angelica Cervantes
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-09-18 → 2021-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018953

## Citation

> US National Institutes of Health, RePORTER application 10018953, Mechanism of Aggregation and Disaggregation of Huntingtin (5F31NS105524-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10018953. Licensed CC0.

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