Modeling Tay-Sachs Disease in Astrocyte-Like Cells Reveals Significant Changes in the Transcriptomic Profile

Progressive GM2storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Although previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons.

However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders.To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells . The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production.