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Targeting DNA mismatch repair in Huntington’s disease
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DOI：10.1016/j.tins.2026.06.004.png)
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Abstract
En 中文
Expansion of the HTT CAG repeat occurs in a cell-type-specific manner, with medium spiny neurons (the cells most prominently lost in Huntington’s disease) showing the most extreme expansions. Critical repeat length thresholds appear to trigger distinct pathogenic stages in these cells. HTT1a—an aberrant HTT transcript encoding a toxic N-terminal protein fragment—is implicated as a key pathogenic effector of CAG repeat expansion, though other toxic HTT-derived species may also contribute. Variants in MMR genes and FAN1 modify somatic HTT CAG repeat expansion and Huntington’s disease phenotypes, representing tractable therapeutic targets with potential for application across other repeat expansion disorders. Human genetics provides insights into the safety considerations of modulating these DNA repair pathways.
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