B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.

Tay-Sachs disease is a severe neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the α-subunit of the β-hexosaminidase A (HexA) enzyme. HexA deficiency leads to abnormal GM2 accumulation, eventually causing cell death and neurodegeneration. A double-knockout mouse model lacking both Hexa and Neu3 genes (Hexa-/-Neu3-/-, DKO) exhibits neuropathological and clinical features similar to those of the disease, including neuroinflammation. B4Galnt1 (ß-1,4-N-acetyl-galactosaminyltransferase 1) is involved in lipid biosynthesis in mice. We hypothesized that creating a triple knockout model (Hexa-/-Neu3-/-B4Galnt1-/-, TKO) could prevent excessive GM2 ganglioside accumulation and reduce disease symptoms. Molecular biology and immunohistochemistry analyses showed that GM2 ganglioside accumulation was halted in TKO mice. Preventing GM2 ganglioside accumulation alleviated neuroinflammation and neuronal death, extending lifespan by more than 18 months. Our findings suggest that knocking out B4Galnt1 to block GM2 ganglioside accumulation may reverse disease symptoms in the DKO mouse model, indicating a promising, safe target for substrate-reduction therapy via siRNA silencing.