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Human Molecular Genetics, 2000, Vol. 9, No. 7 1087-1092
© 2000 Oxford University Press

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

Yujing Liu, Yun-Ping Wu1, Ryuichi Wada, Edward B. Neufeld2, Katherine A. Mullin, April C. Howard, Peter G. Pentchev3, Marie T. Vanier4, Kinuko Suzuki1 and Richard L. Proia+

Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA, 1Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA, 2Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA, 3Developmental and Metabolic Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and 4INSERM Unit 189, Lyon-Sud School of Medicine, 69921 Oullins, France

Niemann–Pick disease Type C (NP-C) is a progressive neurodegenerative disorder 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 the possibility that the accumulation of these lipids may participate in the neurodegenerative process. To determine if ganglioside accumulation is a crucial factor in neuropathogenesis, we bred NP-C model mice with mice carrying a targeted mutation in GalNAcT, the gene encoding the ß-1-4GalNAc transferase responsible for the synthesis of GM2 and complex gangliosides. Unlike the NP-C model mice, these double mutant mice did not exhibit central nervous system (CNS) accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histological analysis revealed that the characteristic neuronal storage pathology of NP-C disease was substantially reduced in the double mutant mice. By contrast, visceral pathology was similar in the NP-C and double mutant mice. Most notably, the clinical phenotype of the double mutant mice, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve. The results demonstrate that complex ganglioside storage, while responsible for much of the neuronal pathology, does not significantly influence the clinical phenotype of the NP-C model.

+ To whom correspondence should be addressed. Tel: +1 301 496 6774; Fax: +1 301 496 9878; Email: proia@nih.gov


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