title: Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease Type C. by affecting sphingolipid metabolism.
abstract: In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NPC mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.
authors.affiliation: Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu 702-701, Korea ; Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Lee
authors.forename: Jong Kil
authors.initials: JK
authors.lastname: Lee
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.forename: Song Hyun
authors.initials: SH
authors.lastname: Yang
authors.forename: Nozomu
authors.initials: N
authors.lastname: Okino
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Bae
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Jin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000473:pathology; D054022:Cerebrum / Q000473:pathology; D004195:Disease Models, Animal; D005679:G(M3) Ganglioside / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology / Q000473:pathology*; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005679:G(M3) Ganglioside; D012799:Sialyltransferases; C021343:haematoside synthetase