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<p>Genome-wide association studies (GWAS) have provided strong evidence that modifiers of CAG tract length have a crucial influence on Huntington disease onset, but somatic expansion alone may not be sufficient to drive neuronal death. Here, we report that DSBs drive neuropathology in male <i>HdhQ(150/150</i>) mice, regardless of somatic expansion of the inherited disease allele. DSBs and somatic expansion occur simultaneously in the HD brain, but the two types of DNA damage drive disease by distinct mechanisms. The site-specific increases in CAG tract length are driven by active mismatch repair (MMR), while DSBs occur genome-wide and are driven by mutant huntingtin-mediated suppression of nonhomologous joining of DNA broken ends. DSBs and transcriptional dysfunction occur in animals that cannot somatically expand their inherited allele. Conversely, suppression of DSBs is sufficient to reverse neuropathology even when somatic expansion is active. We propose that CAG expansion and DSBs promote downstream neuronal pathology as separable drivers. The disease-length CAG tract leads to early inhibition of DSBR and accumulating DSBs over time ultimately kill neurons.</p>

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Double strand breaks drive toxicity in a Huntington’s disease mouse model with or without somatic expansion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • Aris A. Polyzos,
  • Ana Cheong,
  • Jung Hyun Yoo,
  • Lana Blagec,
  • Zachary D. Nagel,
  • Cynthia T. McMurray

摘要

Genome-wide association studies (GWAS) have provided strong evidence that modifiers of CAG tract length have a crucial influence on Huntington disease onset, but somatic expansion alone may not be sufficient to drive neuronal death. Here, we report that DSBs drive neuropathology in male HdhQ(150/150) mice, regardless of somatic expansion of the inherited disease allele. DSBs and somatic expansion occur simultaneously in the HD brain, but the two types of DNA damage drive disease by distinct mechanisms. The site-specific increases in CAG tract length are driven by active mismatch repair (MMR), while DSBs occur genome-wide and are driven by mutant huntingtin-mediated suppression of nonhomologous joining of DNA broken ends. DSBs and transcriptional dysfunction occur in animals that cannot somatically expand their inherited allele. Conversely, suppression of DSBs is sufficient to reverse neuropathology even when somatic expansion is active. We propose that CAG expansion and DSBs promote downstream neuronal pathology as separable drivers. The disease-length CAG tract leads to early inhibition of DSBR and accumulating DSBs over time ultimately kill neurons.