title: Alterations of membrane lipids and in gene expression of ganglioside metabolism in different brain structures in a mouse model of mucopolysaccharidosis type I (MPS I).
abstract: Mucopolysaccharidosis I (MPS I) is a congenital disorder caused by the deficiency of α-l-iduronidase (IDUA), with the accumulation of glycosaminoglycans (GAGs) in the CNS. Although GAG toxicity is not fully understood, previous works suggest a GAG-induced alteration in neuronal membrane composition. This study is aimed to evaluate the levels and distribution of gangliosides and cholesterol in different brain regions (cortex, cerebellum, hippocampus and hypothalamus) in a model using IDUA knockout (KO) mice (C57BL/6). Lipids were extracted with chloroform-methanol and then total gangliosides and cholesterol were determined, followed by ganglioside profile analyses. While no changes in cholesterol content were observed, the results showed a tissue dependent ganglioside alteration in KO mice: a total ganglioside increase in cortex and cerebellum, and a selective presence of GM3, GM2 and GD3 gangliosides in the hippocampus and hypothalamus. To elucidate this, we evaluated gene expression of ganglioside synthesis (GM3, GD3 and GM2/GD2 synthases) and degradation of (Neuraminidase1) enzymes in the cerebellum and hippocampus by RT-sq-PCR. The results obtained with KO mice showed a reduced expression of GD3 and GM2/GD2 synthases and Neuraminidase1 in cerebellum; and a decrease in GM2/GD2 synthase and Neuraminidase1 in the hippocampus. These data suggest that the observed ganglioside changes result from a combined effect of GAGs on ganglioside biosynthesis and degradation.
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica-Instituto de Ciências Básica da Saúde-Universidade Federal do Rio Grande Sul, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kreutz
authors.forename: Fernanda
authors.initials: F
authors.lastname: dos Santos Petry
authors.forename: Melissa
authors.initials: M
authors.lastname: Camassola
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schein
authors.forename: Fátima C R
authors.initials: FC
authors.lastname: Guma
authors.forename: Nance Beyer
authors.initials: NB
authors.lastname: Nardi
authors.forename: Vera Maria Treis
authors.initials: VM
authors.lastname: Trindade
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005677:G(M1) Ganglioside / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000473:pathology; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D008563:Membrane Lipids; D005677:G(M1) Ganglioside; D002784:Cholesterol; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; C021343:haematoside synthetase; C110128:Neu1 protein, mouse; D009439:Neuraminidase
keywords: Alpha-l-iduronidase; CNS; Central Nervous System; GAGs; GD3 synthase; GM2/GD2 synthase; Gangliosides; HPTLC; IDUA; KO; Knockout; MPS I; Mucopolysaccharidosis; Mucopolysaccharidosis I; N-acetyl-neuraminic acid; NANA; Neu1; Neuraminidase 1; Neuraminidase1; RT-sq-PCR; Semi quantitative Polymerase Chain Reaction; TLC; glycosaminoglycans; high performance thin-layer chromatography; thin-layer chromatography; α-l-iduronidase