Subregional brain distribution of simple and complex glycosphingolipids in the mucopolysaccharidosis type I (Hurler syndrome) mouse: impact of diet.
Gangliosides are the most complex oligosaccharide-containing glycosphingolipids defined by the presence of sialic acid and although present in all tissues, predominate in the brain. Considering their importance in neural development, it is unsurprising that ganglioside metabolism is altered in neurodegenerative diseases. The severe form of mucopolysaccharidosis type I, Hurler syndrome (HS), is characterised by progressive loss of neuronal function through largely undefined mechanisms. Here, we sought to interrogate brain gangliosides in a murine model of HS and further, assessed whether dietary modulation of lipid metabolism effected correction of the metabolic abnormalities. The simple gangliosides, GM2, GM3, GD2and GD3were elevated in the five subregions examined - brain stem, cerebellum, cortex, hippocampus, subcortex - in HS mice as early as 2 months of age compared with their wild type counterparts. Their elevation persisted at 6 months of age, imparting protracted neurological development as these simple gangliosides have usually subsided by this stage of brain development. Their immediate synthetic precursor, lactosylceramide, was also elevated, suggesting that their increase arises at this metabolic intermediary, as dihydroceramide, ceramide and monohexosylceramide were unaffected. Dietary linoleic acid supplementation significantly reduced GM2and GM3, and furthermore, improved exploratory behaviour as assessed by the open field test, highlighting the possibility of further exploring dietary intervention as a therapeutic consideration.
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Jennifer T
JT
Saville
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Hong Ngoc
HN
Thai
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Rebecca J
RJ
Lehmann
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Ainslie L K
AL
Derrick-Roberts
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Maria
0000-0001-9092-8942
M
Fuller
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004032:Diet / Q000379:methods*; D005228:Fatty Acids, Essential / Q000008:administration & dosage; D005260:Female; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019787:Linoleic Acid / Q000008:administration & dosage*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000178:diet therapy* / Q000378:metabolism*
D005228:Fatty Acids, Essential; D006028:Glycosphingolipids; D019787:Linoleic Acid
gangliosides; inborn error of metabolism; linoleic acid; mouse model; neurological disease; tandem mass spectrometry