Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse

Niemann-Pick disease Type C (NP-C) is a progressive neurodegenerative disor der caused by mutations in the NPC1 gene and characterized by intracellular accumulation of cholesterol and sphingolipids, The major neuronal storage material in NP-C consists of gangliosides and other glycolipids, raising th e possibility that the accumulation of these lipids may participate in the neurodegenerative process, To determine if ganglioside accumulation is a cr ucial factor in neuropathogenesis, we bred NP-C model mice with mice carryi ng a targeted mutation in GalNAcT, the gene encoding the beta-1-4GalNAc tra nsferase responsible for the synthesis of GM2 and complex gangliosides. Unl ike the NP-C model mice, these double mutant mice did not exhibit central n ervous system (CNS) accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histological analysis revealed that the characteristic neuronal st orage pathology of NP-C disease was substantially reduced in the double mut ant mice, By contrast, visceral pathology was similar in the NP-C and doubl e mutant mice, Most notably, the clinical phenotype of the double mutant mi ce, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve, The results demonstrate that complex gangliosid e storage, while responsible for much of the neuronal pathology, does not s ignificantly influence the clinical phenotype of the NP-C model.