# Molecular mechanisms of triplet repeat instability in Huntington's disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $378,300

## Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion of a CAG repeat tract within
the huntingtin (HTT) gene, leading to neuronal death primarily in the striatum and the cortex. The CAG repeat is
highly unstable and patients with longer inherited CAG repeats develop the disease at an earlier age. The repeat
tract is also highly unstable in somatic cells. A high degree of age-dependent somatic expansion of the CAG
repeat is observed in neurons of both the striatum and the cortex of HD patients, but not in unaffected brain
regions like the cerebellum, indicating that somatic CAG repeat expansion is a driver of disease manifestation.
Earlier disease onset is also associated with the length of uninterrupted CAG repeats and a concomitant increase
in somatic instability. These findings further underscore the importance of somatic CAG expansion in disease
manifestation. Recent genome-wide association studies in affected individuals have revealed the existence of
genetic modifiers of the age of onset of the disease; these include several genes of the mismatch repair pathway
(MMR) (MSH3, MLH1, PMS1, and PMS2) as well as FAN1, a DNA interstrand cross-link repair gene.
Independently, studies in mouse models of HD have revealed that genetic knockout of the MMR genes, Msh2,
Msh3, or Mlh1 reduces somatic instability of CAG repeats in the striatum. A role for MMR (the canonical function
of which is to maintain genomic stability) in CAG repeat expansion is further supported by the observation that
proteins in this pathway recognize and process extrahelical DNA extrusions formed by mishybridization of the
two repeat-containing DNA strands. These findings support the view that aberrant MMR of such extrusions
underlies the repeat expansion process. By contrast, knockout of Fan1 in an HD mouse model exacerbates CAG
repeat expansion. We therefore hypothesize that two opposing DNA repair mechanisms act on CAG extrusions.
Because MMR promotes repeat expansion, and FAN1 attenuates CAG expansion, the balance between these
opposing pathways in affected neuronal cells likely determines the rate of repeat expansion and consequently,
disease manifestation. Since the molecular details of either of these processes remains unclear, our overarching
goal is to integrate biochemical, cellular, and phenotypic studies to develop a unified understanding of the
mechanism of tissue/cell type specific CAG repeat expansion. In Aim 1, we will compare and contrast the
molecular features and differing outcomes of the MutSβ- and FAN1- initiated CAG extrusion repair pathways. In
Aim 2, we will determine the functional significance of protein complexes that associate with CAG extrusions. In
Aim 3, we will define the role of PMS1 (as part of the MutLβ heterodimer) in regulation of CAG extrusion repair
and repeat expansion. Completion of these studies will not only shed light on the mechanisms of CAG repeat
expansion in HD, but also will inform our understanding of the...

## Key facts

- **NIH application ID:** 10878982
- **Project number:** 5R01NS118082-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Anna Pluciennik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,300
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878982

## Citation

> US National Institutes of Health, RePORTER application 10878982, Molecular mechanisms of triplet repeat instability in Huntington's disease (5R01NS118082-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10878982. Licensed CC0.

---

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