# Effect of small peptide binders on huntingtin fibrillization and toxicity

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Huntington’s disease is a progressive neurodegenerative disorder caused by a mutation in exon1 of the
huntingtin protein (mHttex1), which causes the protein to fibrillize and aggregate. While the exact genetic basis
of this disease has been known for decades, there is still no cure or effective clinical treatment. Therapeutic
development is complicated by the fact that it is unclear how mHttex1 exerts its toxic effects. Structural studies
have revealed mHttex1 monomer aggregates in a stepwise manner, misfolding into several intermediate
structures before eventually forming the fibrillar aggregates characteristic of the disease. Previous studies have
also shown that some of these intermediate conformers, such as protofibrils, are toxic. To better understand
these structures, the Langen lab collaborated with Dr. Richard Roberts to make small peptide binders for
protofibrils. Our first set of peptide binders, HD1 and HD8, have shown a high affinity for not only these toxic
protofibrils, but also with mHttex1 oligomers, another early mHttex1 conformer posited to be toxic. Even more
exciting, our binders appear to prevent a phenomenon known as “seeding,” where introducing a small amount
of misfolded mHttex1 will accelerate fibrillization of mHttex1 monomer through template-assisted misfolding. In
this proposal, I will leverage our novel peptide binders to learn how HD1 and HD8 prevent seeding of mHttex1
monomer, and what effect these peptide binders will have on mHttex1 aggregation and toxicity. In Aim 1, I will
use a combination of biophysical methods such as electron paramagnetic resonance (EPR), solid-state nuclear
magnetic resonance (ssNMR), and a new fluorescence microscopy application to monitor fibril growth in real
time. These experiments will reveal both the seeding inhibition mechanism of HD1 and HD8 as well as structural
information of these peptide binders, which will be important for developing future treatments. Additionally,
preliminary evidence shows that co-expressing mHttex1 with HD1 or HD8 in cell culture decreases the amount
of overall mHttex1. Using both cell culture and mouse models of Huntington’s disease, Aim 2 will explore how
HD1 and HD8 interact with mHttex1 within the cell and whether these peptide binders can rescue the deleterious
effects of mHttex1. These experiments will provide a picture of how exactly HD1 and HD8 exert their effects on
mHttex1 and evaluate the therapeutic potential of these peptide binders.

## Key facts

- **NIH application ID:** 10465971
- **Project number:** 1F31NS125994-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Elissa Fultz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-06-20 → 2024-06-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465971

## Citation

> US National Institutes of Health, RePORTER application 10465971, Effect of small peptide binders on huntingtin fibrillization and toxicity (1F31NS125994-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465971. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*