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

Tay-Sachs disease is a severe lysosomal storage disorder caused bymutations in the HEXA gene coding fora subunit of lysosomal beta-Hexosaminidase A enzyme, which converts G(M2) to G(M3) ganglioside. HexA(-/-)mice, depleted of the beta-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 beta-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 inmouse. 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 neuraminidase/neuraminidases such as Neu2 and/or Neu3 might be also involved in the ganglioside degradation pathway in HexA(-/-)mice. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license