Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay–Sachs mouse models

摘要

Tay–Sachs disease is a severe lysosomal storage disorder caused by mutations in the HEXA gene coding for α subunit of lysosomal β-Hexosaminidase A enzyme, which converts G_M2 to G_M3 ganglioside. HexA?/? mice, depleted of the β-Hexosaminidase A iso-enzyme, remain asymptomatic up to 1 year of age because of a metabolic bypass by neuraminidase(s). These enzymes remove a sialic acid residue converting G_M2 to G_A2, which is further degraded by the still intact β-Hexosaminidase B iso-enzyme into lactosylceramide. A previously identified ganglioside metabolizing neuraminidase, Neu4, is abundantly expressed in the mouse brain and has activity against gangliosides like G_M2 in vitro . Neu4?/? mice showed increased G_D1a and decreased G_M1 ganglioside in the brain suggesting the importance of the Neu4 in ganglioside catabolism. Mice with targeted disruption of both HexA and Neu4 genes showed accumulating G_M2 ganglioside and epileptic seizures with 40% penetrance, indicating that the neuraminidase Neu4 is a modulatory gene, but may not be the only neuraminidase contributing to the metabolic bypass in HexA?/? mice. Therefore, we elucidated the biological role of neuraminidase-1 in ganglioside degradation in mouse. Analysis of HexA?/? Neu1?/? and HexA?/? Neu4?/? Neu1?/? mice models showed significant contribution of neuraminidase-1 on B-series ganglioside degradation in the brain. Therefore, we speculate that other neuraminidaseeuraminidases such as Neu2 and/or Neu3 might be also involved in the ganglioside degradation pathway in HexA?/? mice.