Lipid Composition of Whole Brain and Cerebellum in Hurler Syndrome (MPS IH) Mice

Heinecke, Karie A.; Peacock, Brandon; Blazar, Bruce R.; Tolar, Jakub; Seyfried, Thomas N.

doi:10.1007/s11064-011-0400-y

Cited by 7 publications

(7 citation statements)

References 65 publications

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“…Our lipid characterisation of the HS mice brain is broadly in agreement with the seminal findings of Heinecke et al . () – using the same mouse model – who also demonstrated increases in G M2 , G M3 and G D3 with a general preservation in other lipid species, including the ceramides and sulfatides. Discrepancies between the two data sets can largely be explained by the different methodologies employed; LC‐ESI‐MS/MS compared with TLC.…”

Section: Discussionmentioning

confidence: 71%

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

Saville

Thai

Lehmann

et al. 2017

Journal of Neurochemistry

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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, G M2 , G M3 , G D2 and G D3 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 G M2 and G M3 , and furthermore, improved exploratory behaviour as assessed by the open field test, highlighting the possibility of further exploring dietary intervention as a therapeutic consideration. Keywords: gangliosides, inborn error of metabolism, linoleic acid, mouse model, neurological disease, tandem mass spectrometry.

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Section: Discussionmentioning

confidence: 71%

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

Saville

Thai

Lehmann

et al. 2017

Journal of Neurochemistry

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“…The enzyme IDUA catalyzes breakdown of glycosaminoglycans (GAGs) containing α-L-iduronic acid [ 41 ]. Absence of IDUA in MPS I leads to accumulation of various gangliosides in brain and other tissues [ 19 , 42 ]. Of these gangliosides, GD3 and GM1 are enriched in oligodendrocytes and myelin membranes [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Dysmyelination with RAFFn MRI: Application to Murine MPS I

et al. 2015

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Type I mucopolysaccharidosis (MPS I) is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T 1ρ, and T 2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule (P = 0.039), and marginally larger for the fornix (P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.

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“…Complete lipid isolation, purification, and quantitation have been previously described ( Seyfried et al., 1978 ; Hauser et al., 2004 ; Kasperzyk et al., 2004 ; Heinecke et al., 2011 ) and are briefly described as follows. Lipids were extracted from lyophilized nerve tissue.…”

Section: Methodsmentioning

confidence: 99%

“…Lipids were extracted from lyophilized nerve tissue. Neutral lipids and acidic lipids were separated using DEAE-Sephadex (A-25, Pharmacia Biotech, Upsala, Sweden) column chromatography as previously described ( Macala et al., 1983 ; Heinecke et al., 2011 ). The entire neutral lipid fraction was collected and contained cerebrosides and asialo-ganglioside GM1 (GA1).…”

Section: Methodsmentioning

confidence: 99%

“…Samples and standards were analyzed in the Shimadzu UV-1601 ultraviolet-visible spectrophotometer (Shimadzu, Kyoto, Japan). The ganglioside fraction was further purified with base treatment and desalting after Folch partitioning ( Hauser et al., 2004 ; Kasperzyk et al., 2004 ; Heinecke et al., 2011 ). Gangliosides were eluted from C18 reverse-phase Bond Elute columns (Varian, Harbor City, CA), evaporated under N 2 , and resuspended in CHCl 3 : CH 3 OH (1:1 by volume).…”

Section: Methodsmentioning

confidence: 99%

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Myelin Abnormalities in the Optic and Sciatic Nerves in Mice With GM1-Gangliosidosis

et al. 2015

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GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old β-galactosidase (β-gal) +/? and β-gal −/− mice, a model of GM1gangliosidosis. Optic nerve weight was lower in the β-gal −/− mice than in unaffected β-gal +/? mice, but no difference was seen in sciatic nerve weight. The levels of GM1 and GA1 were significantly increased in both the optic nerve and sciatic nerve of the β-gal −/− mice. The content of myelin-enriched cerebrosides, sulfatides, and plasmalogen ethanolamines was significantly lower in optic nerve of β-gal −/− mice than in β-gal +/? mice; however, cholesteryl esters were enriched in the β-gal −/− mice. No major abnormalities in these lipids were detected in the sciatic nerve of the β-gal −/− mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal −/− mice correlated with a reduction in the relative amount of myelin and periodicity in fresh nerve. By contrast, the relative amount of myelin and periodicity in the sciatic nerves from control and β-gal −/− mice were indistinguishable, suggesting minimal pathological involvement in sciatic nerve. Our results indicate that the greater neurochemical pathology observed in the optic nerve than in the sciatic nerve of β-gal −/− mice is likely due to the greater glycolipid storage in optic nerve.

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Lipid Composition of Whole Brain and Cerebellum in Hurler Syndrome (MPS IH) Mice

Cited by 7 publications

References 65 publications

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

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

Assessment of Dysmyelination with RAFFn MRI: Application to Murine MPS I

Myelin Abnormalities in the Optic and Sciatic Nerves in Mice With GM1-Gangliosidosis

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