GM1 gangliosidosis is a
neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-
galactosidase. The
enzyme deficiency blocks
GM1 ganglioside catabolism, leading to accumulation of
GM1 ganglioside and asialo-GM1
ganglioside (GA1
glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-
galactosidase activity primarily determining the
clinical course. Glb1 null mouse models, which completely lack β-
galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the
GM1 ganglioside degradation pathway. We hypothesized this difference may involve the
sialidase NEU3, which acts on
GM1 ganglioside to produce GA1
glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe
ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased
GM1 ganglioside to GA1
glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated
GM1 ganglioside to GA1
glycolipid conversion in Glb1 KO mice. The expression of genes associated with
neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted
GM1 ganglioside to GA1
glycolipid than human NEU3 did. Our findings highlight NEU3's role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3's differential effects between mice and humans in
GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic
GM1 ganglioside accumulation in
GM1 gangliosidosis patients.