Astrocyte heterogeneity and gliosis in Huntington's disease: Histopathological insights into striatal and white matter pathology.

Huntington's disease (HD) is a devastating, autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Among the major pathological hallmarks of HD are mutant huntingtin aggregation, white matter loss and reactive astrogliosis, which together contribute to neuronal dysfunction and death, particularly in the striatum and cortex. Recent studies in HD mouse models have identified a specialized astrocyte subtype that clusters around white matter bundles originating from the secondary cortex and passing through the striatum. While the functional role of these astrocytes remains unclear, they express Glial Fibrillary Acidic Protein (GFAP), a marker typically associated with both fibrous and reactive astrocytes. The discovery of this white matter-associated astrocyte subtype, along with other astrocytic subtypes differing between grey and white matter, underscores the complexity of glial responses in HD. Accurate identification and interpretation of these glial populations are crucial for understanding disease mechanisms and progression. Given the overlapping expression profiles of commonly used astrocyte markers like GFAP, the careful selection and application of both astrocyte and white matter markers in histopathological analyses are essential to advance our understanding of how glial cells contribute to HD pathology. In this review we discuss different histopathological approaches to assess the roles of glia in HD, emphasizing the need for standardized approaches and critical evaluation of marker specificity.