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Targeting DNA mismatch repair in Huntington's disease

Emma L Bunting1, Amol Panhale2, Peter McColgan1

  • 1Roche Products Ltd, Welwyn Garden City, UK.

Trends in Neurosciences
|July 11, 2026
PubMed

Insights

Huntington's disease (HD) involves harmful HTT CAG repeat expansion, driven by DNA repair errors. Targeting mismatch repair (MMR) proteins may slow this expansion, offering a potential therapeutic strategy for HD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) pathogenesis is characterized by somatic expansion of the HTT CAG repeat.
  • Mismatch repair (MMR) enzymes are implicated in driving this expansion through erroneous DNA repair.
  • Genetic variations in MMR genes influence HD onset and progression.

Purpose of the Study:

  • To synthesize current knowledge on CAG repeat-length-dependent changes in HD.
  • To evaluate key MMR proteins (MSH3, MLH3, PMS1) as therapeutic targets.
  • To outline safety considerations for MMR-modulating therapies.

Main Methods:

  • Review of post-mortem brain tissue studies.
  • Analysis of cell system data.
  • Examination of findings from mouse models of HD.

Main Results:

  • Confirmed elevated somatic expansion in medium spiny neurons, linked to HD vulnerability.
  • Identified specific CAG repeat expansion thresholds associated with cellular pathogenesis stages.
  • Detailed CAG repeat-length-dependent molecular and cellular alterations.

Conclusions:

  • Somatic expansion of the HTT CAG repeat is a critical factor in HD.
  • MSH3, MLH3, and PMS1 are promising therapeutic targets for reducing somatic expansion.
  • Careful consideration of safety is essential for MMR-modulating therapeutic approaches in HD.

Keywords:
genetic modifiersmicrosatellite instabilitypolyposissomatic expansiontherapeutic targetstranscriptionopathy

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