Targeting DNA mismatch repair in Huntington's disease.

Authors

Emma L Bunting, Amol Panhale, Peter McColgan, Minoru Koi, Patrik Brundin, John M Carethers

Published in

Trends in neurosciences. Jul 11, 2026. Epub Jul 11, 2026.

Abstract

Somatic expansion of the HTT CAG repeat is a key feature of Huntington's disease (HD) pathogenesis. Mismatch repair (MMR) enzymes drive this process through erroneous DNA repair, with variants in MMR genes modifying the onset and progression of disease features. Cell-type-specific CAG repeat sizing recently confirmed that elevated somatic expansion underlies the selective vulnerability of HD medium spiny neurons, with expansion beyond certain CAG thresholds associated with distinct stages of cellular pathogenesis. In this review, we synthesise insights from post-mortem brain tissue, cell systems, and mouse models, detailing key CAG repeat-length-dependent changes. In addition, we critically evaluate the MMR proteins MSH3, MLH3, and PMS1 as therapeutic targets for slowing somatic expansion and outline key safety considerations for emerging MMR-modulating approaches.

PMID:
42436050
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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