Rethinking Spinocerebellar Ataxia Type 1: A Glial Perspective Beyond Purkinje Cell Degeneration

More than 30 years after the discovery of the genetic cause of spinocerebellar ataxia type 1 (SCA1), selective Purkinje cell vulnerability remains a defining feature of disease pathogenesis. Increasing evidence also implicates glial cells, including oligodendroglia, astroglia, and microglia, as important contributors to neurodegeneration in SCA1 and other ataxias. In this review, we summarize current evidence for the mechanisms through which glia contribute to SCA1 progression and pathology. Early oligodendroglial dys-function leads to cell-autonomous myelination deficits and non-cell-autonomous im-pairments in Purkinje cell axonal health. Astroglial dysfunction, particularly in Berg-mann glia, disrupts glutamate homeostasis and is associated with aberrant activation of NF-κβ, JNK, and Wnt/β-catenin signaling pathways. Although microglial involvement in SCA1 remains less well understood, microglial activation appears to be regionally re-stricted to the cerebellum and inferior olive. Studies of microglial depletion have yielded partial and, in some cases, conflicting functional outcomes. Notably, dysregulated Wnt/β-catenin signaling across all three glial subtypes may represent a unifying mechanism. Together, these findings identify glia as active, region-specific contributors to SCA1 pathogenesis and highlight underexplored opportunities for mechanistic and therapeutic investigation in polyglutamine diseases.