# Molecular Mechanisms of Pathogenesis in Huntington’s disease

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $1,125,467

## Abstract

Huntington’s disease (HD), one of the first neurodegenerative diseases for which a genetic cause
was determined, is an inherited neurodegenerative disorder that has no disease-modifying
treatment. HD is caused by a CAG repeat expansion in the HTT gene encoding a polyglutamine
(polyQ) tract within the amino terminal portion of Huntingtin (HTT). While the field has gained an
understanding of the many cellular processes that are disrupted in HD, we do not yet understand
the interplay between key proximal HD-associated events, such as the relationship between
aberrant mutant HTT (mHTT) accumulation, RNA biology and epigenetic events in specific cell
types in the brain. Similarly, we do not know how changes in these processes impact clinical
manifestation of disease, where best to intervene therapeutically and what outcome measures
may be the most informative in HD models. The overarching focus of the research proposed here
is to fill vital gaps in our knowledge about how these factors impact onset and progression of HD
and how that understanding might lead to new disease-altering therapies. The proposed research
will leverage unique resources and methods developed in my lab and those of my collaborators
and will utilize state-of-the-art technologies such as single-cell RNA-seq, mass spectrometry and
cryo-electron tomography to dissect molecular mechanisms. Ultimately, treatments for this
disease, including combination therapies, will likely require a much better fundamental
understanding of how mHTT leads to HD pathology and death. Our recent data suggests
unexpected relationships between protein posttranslational modification (PTM) pathways,
aberrant mutant HTT accumulation and DNA damage responses in neurons, the latter now
implicated as a critical modifier of HD age-of-onset. Using a systems biology approach we are
learning how chronic expression and accumulation of mHTT impacts gene expression and now
seek to develop a more comprehensive understanding of RNA biology and causal networks in
specific cell types. Here I propose investigations aimed at addressing major gaps in our
understanding of how the fundamental molecular and cellular events underlie how the mutant HD
gene causes degeneration of specific cell populations in the brain to induce motor and cognitive
decline and ultimately premature death of patients. My program benefits from the integrated use
of patient iPSCs and HD mouse models and the extensive and productive collaborations we have
established over many years. With the overall goal of understanding proximal and initiating events
in the disease and developing therapies for HD, I propose two primary avenues of research
relating to the integration of 1) protein homeostasis and 2) epigenetics and RNA biology in HD.

## Key facts

- **NIH application ID:** 9986383
- **Project number:** 1R35NS116872-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Leslie Michels Thompson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,125,467
- **Award type:** 1
- **Project period:** 2020-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986383

## Citation

> US National Institutes of Health, RePORTER application 9986383, Molecular Mechanisms of Pathogenesis in Huntington’s disease (1R35NS116872-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986383. Licensed CC0.

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