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<p>Huntington's disease (HD) is an inherited neurodegenerative disorder caused by poly-glutamine expansion in the mutant huntingtin (mHTT) protein. While the pathogenesis involves both cell-autonomous and non-cell-autonomous mechanisms, the role of specific intercellular crosstalk in HD remains unclear. The PLP-150Q mouse model, which expresses mHTT selectively in oligodendrocytes, serves as an excellent platform for studying the progression of HD in these cells. RNA sequencing of PLP-150Q mouse brains revealed significant alterations in immune-inflammatory pathways and glial dysfunction, particularly in the corpus callosum and striatum. Notably, we observed an age-dependent upregulation of key inflammatory factors specifically within the corpus callosum. Western blot and immunohistochemical analyses further demonstrated reactive gliosis, characterized by elevated Iba1<sup>+</sup> and CD68<sup>+</sup> microglia, as well as GFAP⁺ and S100β<sup>+</sup> astrocytes, alongside decreased myelin protein levels. Our findings suggest that mHTT in oligodendrocytes triggers age-dependent inflammation, contributing to HD progression and revealing new mechanisms in its pathogenesis.</p>

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Oligodendroglial Mutant Huntingtin Contributes to Neuroinflammation in Huntington’s Disease Mice

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Xinhui Li,
  • Gongke Zhou,
  • Shuying Xu,
  • Tianqi Yang,
  • Shurui Yin,
  • Sitong Yang,
  • Yi Wu,
  • Xinqi Zhou,
  • Su Yang,
  • Huichun Tong,
  • Xiao-Jiang Li,
  • Shihua Li

摘要

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by poly-glutamine expansion in the mutant huntingtin (mHTT) protein. While the pathogenesis involves both cell-autonomous and non-cell-autonomous mechanisms, the role of specific intercellular crosstalk in HD remains unclear. The PLP-150Q mouse model, which expresses mHTT selectively in oligodendrocytes, serves as an excellent platform for studying the progression of HD in these cells. RNA sequencing of PLP-150Q mouse brains revealed significant alterations in immune-inflammatory pathways and glial dysfunction, particularly in the corpus callosum and striatum. Notably, we observed an age-dependent upregulation of key inflammatory factors specifically within the corpus callosum. Western blot and immunohistochemical analyses further demonstrated reactive gliosis, characterized by elevated Iba1+ and CD68+ microglia, as well as GFAP⁺ and S100β+ astrocytes, alongside decreased myelin protein levels. Our findings suggest that mHTT in oligodendrocytes triggers age-dependent inflammation, contributing to HD progression and revealing new mechanisms in its pathogenesis.