Oligodendroglial Mutant Huntingtin Contributes to Neuroinflammation in Huntington's Disease Mice.

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.