# Novel mouse genetic models to study modifiers of Huntington’s disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $642,984

## Abstract

PROJECT SUMMARY
Huntington's disease (HD) is one of the most common autosomal dominant neurodegenerative disorders
affecting 30,000 patients in the US. HD patients typically experience motor, cognitive and psychiatric
symptoms, which is associated with the loss of the striatal and cortical neurons. The disease inexorably
progresses after the onset and patients typically succumb to the disease about 10-20 years after disease
onset. HD is caused by a CAG repeat expansion, that encodes a polyglutamine repeat, in mutant Huntingtin
(mHTT). Currently, there is no treatment to prevent the onset or slow the progression of HD.
A recent genome wide association study (GWAS) identified several loci associated with modification of HD age
of disease onset. The most significant loci identified were in Chr. 15 and encompasses a DNA repair enzyme
called FAN1. Interestingly, FAN1 and two other genes identified in the HD modifier GWAS (MLH1 and MSH3)
are all implicated in the instability of mHTT CAG repeat in somatic tissues. However, it is unclear whether
FAN1's roles in CAG repeat instability is related to its function as a modifier of HD pathology including
behavioral impairment (locomotor activity, sleep disturbance), striatal and cortical neuronal electrophysiological
and pathological changes, and transcriptional dysregulation.
In this proposal, we will address these critical questions using two HD mouse models, the Q140 murine Htt
knockin model and a novel human genomic BAC transgenic mouse model of HD with >120 pure CAG repeats.
The latter model is the first human mHTT model that shows CAG repeat instability that is correlated with
behavioral deficits, and robust striatum-selective transcriptional dysregulation. We will cross these two HD
mouse models with novel Fan1/FAN1 genetic models to address the following key questions: 1. Does reducing
endogenous murine Fan1 levels accelerate the pathogenesis in the two HD mouse models (Aim 1)? 2. Do
mice with murine Fan1-R510H knockin alleles (equivalent to the human patient-derived, deleterious FAN1
variant R507H) show disease-exacerbating effects, similar to the Fan1 knockdown mice (Aim 2)? and 3.
Whether genetic mouse models with elevated expression of human FAN1 (BAC-FAN1) can ameliorate the
behavioral, electrophysiological, pathological and molecular (i.e. transcriptomic) phenotypes in the two HD
mouse models (Aim 3)?
The findings from our study will be crucial to unravel where in the brain and what molecular mechanisms
underly how Fan1 mutants modify HD pathogenesis in vivo. Furthermore, the mouse resources we have
developed and the phenotyping platforms that will use in this study will be invaluable to future investigations of
other HD modifiers and for developing therapeutics to target the HD human genetic modifiers to prevent, slow
or stop progression of HD.

## Key facts

- **NIH application ID:** 10210455
- **Project number:** 5R01NS113612-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Xiangdong William Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,984
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210455

## Citation

> US National Institutes of Health, RePORTER application 10210455, Novel mouse genetic models to study modifiers of Huntington’s disease (5R01NS113612-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10210455. Licensed CC0.

---

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