Xinhui Li1  · Gongke Zhou1  · Shuying Xu1  · Tianqi Yang1  · Shurui Yin1  · Sitong Yang1  · Yi Wu1  · Xinqi Zhou1  · Su Yang1  · Huichun Tong1,3 · Xiao‑Jiang Li1,2 · Shihua Li1

1 Guangdong Key Laboratory of Non‑human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China 

2 Lingang Laboratory, Shanghai 201103, China 

3 Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China

Abstract

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.

Keywords

Huntington’s disease; Oligodendrocytes; Mutant huntingtin protein; Neuroinflammation; Polyglutamine expansion

[SpringerLink]