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.

Public Health Relevance

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the United States. Currently, HD is not treatable or curable, and the patients invariably suffer from the motor, cognitive and psychiatric symptoms that relentlessly progress toward an eventual bedridden state and death about 10-20 years after the disease onset. Our proposed study will focus on a gene (FAN1) that is shown to modify HD age of disease onset in the patients. Our study will use HD mouse models to study how Fan1 gene defects may accelerate the disease, and test whether elevated FAN1 levels can delay the onset or reduce the severity of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS113612-02
Application #
9968458
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Daniel L
Project Start
2019-07-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095