Subregional brain distribution of simple and complex glycosphingolipids in the mucopolysaccharidosis type I (Hurler syndrome) mouse: impact of diet

• Published in: Journal of neurochemistry 2017-04, Vol.141 (2), p.287-295
• Main Authors: Saville, Jennifer T., Thai, Hong Ngoc, Lehmann, Rebecca J., Derrick‐Roberts, Ainslie L. K., Fuller, Maria
• Format: Article
• Language: English
• Subjects: Animals; Brain - drug effects; Brain - metabolism; Diet; Diet - methods; Fatty Acids, Essential - administration & dosage; Female; gangliosides; Genetic disorders; Glycosphingolipids - antagonists & inhibitors; Glycosphingolipids - metabolism; inborn error of metabolism; linoleic acid; Linoleic Acid - administration & dosage; Lipids; Locomotion - drug effects; Locomotion - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mouse model; Mucopolysaccharidosis I - diet therapy; Mucopolysaccharidosis I - metabolism; Neurochemistry; neurological disease; Neurological disorders; tandem mass spectrometry
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13976

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, GD2 and GD3 were 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 GM2 and 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. Gangliosides are complex glycosphingolipids characterised by the presence of sialic acid and are vital in proper brain development. Here, we interrogated subregional brain gangliosides in a murine model of Hurler syndrome (HS) and tested whether dietary supplementation of linoleic acid corrected the abnormal gangliosides and improved locomotor behaviour as assessed by the open field test. Simple gangliosides and the immediate precursor, lactosylceramide were elevated in the brain subregions of HS mice and a diet high in linoleic acid reduced these lipids – although did not completely normalise the concentrations – with a concomitant improvement in locomotor activity.