Impact of Sinbaglustat on Neurons of the Medial Nucleus of the Trapezoid Body in a Murine Model of Human GM1-Gangliosidosis.

Background: GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the Glb1 gene, resulting in reduced β-galactosidase activity and accumulation of GM1 gangliosides in neuronal lysosomes. Effective therapeutic strategies for this disease remain limited. Substrate reduction therapy using small molecules targeting glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GBA2), such as sinbaglustat, represents a promising approach. Methods: Structural and electrophysiological properties of principal neurons of the medial nucleus of the trapezoid body (MNTB) were investigated in 7-month-old Glb1-/- mice. Animals received long-term treatment with either low (LD; 10 mg/kg) or high (HD; 300 mg/kg) doses of sinbaglustat and were compared with untreated Glb1-/- (KO) and untreated wild-type (WT) mice. Results: Sinbaglustat treatment reduced lysosomal storage material in MNTB neurons. Basal membrane properties were largely unchanged across groups. However, action potential halfwidth was significantly increased in untreated KO and LD mice compared to untreated WT animals but was normalized in HD mice. After-hyperpolarization duration was prolonged in Glb1-/- mice relative to WT. Temporal precision during high-frequency stimulation was reduced in untreated KO mice and improved following sinbaglustat treatment. Conclusions: These findings indicate that GM1-gangliosidosis is associated with functional alterations in MNTB neurons and suggest that long-term sinbaglustat treatment can partially restore neuronal electrophysiological properties, supporting its therapeutic potential in GM1.