# Dissecting the role of DNA Ligase 1 in Huntington's disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $640,064

## Abstract

Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a
polymorphic CAG repeat in the HTT gene. Although the underlying genetic mutation was discovered over 25
years ago, there is still no cure or effective treatment despite extensive efforts. The CAG repeat mutation
undergoes time- and CAG length-dependent somatic expansion and recent genome-wide association studies
(GWAS) support somatic CAG expansion as the first step of the pathogenic process, required to elicit cellular
toxicity and ultimately clinical disease. GWAS identified several genes involved in DNA repair as modifiers of
age of onset, among which is LIG1, encoding DNA ligase 1. The biological function of DNA ligase 1 implicates
it in somatic CAG expansion, however this gene may also alter processes that impact on cellular toxicity.
Overall, the mechanistic underpinnings of disease modification remain obscure. Independent LIG1 modifier
chromosomes can be distinguished in the human genetic data: one, tagged by a predicted deleterious SNP
encoding a K854N substitution, is onset-delaying, while another is associated with increased LIG1 expression
and is onset-hastening. In this study, we will perform experiments to test hypotheses rooted in human genetic
data to understand the functional consequences of these LIG1 modifier effects. In Aim 1 we will use a knock-in
mouse model of HD to test the impact of the K>N substitution mutation introduced into the mouse Lig1 gene,
and to test the impact of Lig1 upregulation, on somatic CAG expansion and phenotypic expression. In Aim 2
we will use HD patient-derived and isogenic neuronal progenitor cells and neurons harboring LIG1 modifier
alleles to identify their cellular and molecular consequences and to test their impacts on phenotypes elicited by
the HTT mutation. In Aim 3 we will perform biochemical, structural and functional analyses of the LIG1 K845N
variant. Together, these experiments will provide novel insight into mechanisms by which genetic variation in
LIG1 modifies disease in patients, ultimately revealing therapeutic avenues that can be pursued for disease-
modifying treatments.

## Key facts

- **NIH application ID:** 10892912
- **Project number:** 5R01NS127866-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ihn Sik Seong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,064
- **Award type:** 5
- **Project period:** 2023-07-25 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892912

## Citation

> US National Institutes of Health, RePORTER application 10892912, Dissecting the role of DNA Ligase 1 in Huntington's disease (5R01NS127866-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892912. Licensed CC0.

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