Striatal astrocyte μ-crystallin (Crym) loss contributes to early-stage Huntington's disease pathophysiology.

A striatal astrocyte subpopulation expressing μ-crystallin (gene: Crym) regulates perseverative behaviors, but its role in disease is unclear. We found that astrocytic Crym and μ-crystallin protein expression levels are reduced in human Huntington's disease (HD) tissue, cerebrospinal fluid, and HD mouse models. Selective astrocytic μ-crystallin restoration in a HD mouse model improved astrocyte and neuronal morphology, electrophysiology, gene expression, and early-stage compulsive and repetitive behaviors. Late-stage motor deficits remained mostly unchanged. Approximately 32% of the μ-crystallin rescued astrocytic genes overlapped with those dysregulated in human HD, indicating conserved molecular corrections. These results identify μ-crystallin-expressing astrocytes as modulators of HD pathophysiology and suggest that restoring μ-crystallin or targeting Crym-positive astrocytes could be beneficial in early disease stages.