# Neuronal DNA repair pathways in Huntington's disease pathophysiology

> **NIH NIH R03** · THOMAS JEFFERSON UNIVERSITY · 2020 · $78,000

## 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, both intergenerationally and in somatic cells. HD patients display a high degree of age-
dependent somatic expansion of the CAG repeat in the striatum, although such expansions also occur in other
tissues. Recent genome-wide association studies of HD patients have revealed the existence of genetic
modifiers of the age of onset of the disease; these include several genes involved in DNA repair, and in particular
DNA mismatch repair (MSH3, MLH1, PMS2, PMS1). In addition, studies in mouse models of HD have revealed
that genetic knockout of the DNA mismatch repair genes, Msh2, Msh3, Mlh1, or Mlh3 reduces somatic instability
of CAG repeats in the striatum. These data suggest that somatic expansion of CAG repeats is likely linked to
striatal neuronal loss, and onset of disease symptoms in HD patients. Therefore, in Aim 1, we propose to
characterize and compare protein assemblies in mouse striatum and other mouse brain regions that recognize
and process CAG extrusions. We anticipate that these protein complexes may shed light on the mechanism of
CAG expansions, while also potentially uncovering novel pathological processes unrelated to repeat instability.
In Aim 2, we will develop proximity biotinylation (TurboID)-based assay in human HEK293 cells to evaluate
transient and stable protein assemblies on DNA containing CAG extrusions, with a view to eventually applying
this approach to cells of neuronal origin. The effects of knockdown of critical mismatch repair genes like MSH3
or FAN1 on the processing of such DNA lesions will also be evaluated. The objective of these approaches is to
identify proteins that determine whether CAG extrusions are processed by FAN1 or the mismatch repair pathway.

## Key facts

- **NIH application ID:** 10019604
- **Project number:** 5R03NS114976-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Anna Pluciennik
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,000
- **Award type:** 5
- **Project period:** 2019-09-17 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019604

## Citation

> US National Institutes of Health, RePORTER application 10019604, Neuronal DNA repair pathways in Huntington's disease pathophysiology (5R03NS114976-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10019604. Licensed CC0.

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