Hepatic storage of oligosaccharides and glycolipids in a cat affected with GM1 gangliosidosis

Holmes, Earle W.; O’Brien, John S.

doi:10.1042/bj1750945

Cited by 15 publications

(7 citation statements)

References 31 publications

(32 reference statements)

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“…The postulated structures ofthe oligosaccharide storage products found in the affected animal are consistent with the incomplete catabolism of glycoproteins as a result of a deficiency of fl-Dgalactosidase. The structures proposed for compounds (1) and (2) have the same composition as the storage products in feline GM, gangliosidosis in Siamese kittens (Holmes & O'Brien, 1978b) and are identical with those proposed for the storage products in canine GM, gangliosidosis (Warner & O'Brien, 1982). The structures are also similar to compounds isolated from human-GM1-gangliosidosis liver and urine, except that the latter terminate in a single N-acetylglucosamine residue at the reducing end.…”

Section: Discussionsupporting

confidence: 62%

See 1 more Smart Citation

GM1 gangliosidosis (type 1) in a cat

Barker¹,

Blakemore²,

Dell³

et al. 1986

Biochemical Journal

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A kitten with clinical and morphological symptoms of a neurovisceral lysosomal-storage disease has been shown to have a marked deficiency of acidic beta-D-galactosidase in the brain, kidney and spleen. Chromatography on concanavalin A-Sepharose and inhibition studies with 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine, a selective inhibitor of the neutral broad-specificity beta-D-galactosidase, have shown that the residual beta-D-galactosidase at pH 4.0 in the tissues of the affected cat is due to the neutral beta-D-galactosidase and that there is a complete deficiency of the acidic (lysosomal) beta-D-galactosidase. There is marked accumulation in all tissues and excretion in the urine of neutral oligosaccharides. Analysis of these oligosaccharides by fast-atom-bombardment mass spectrometry and g.l.c. suggests that they arise from the incomplete catabolism of N-glycans of glycoproteins. The ganglioside content of all the tissues is elevated, and it has been shown by t.l.c. that the concentration of a ganglioside fraction with a mobility similar to that of GM1 ganglioside is particularly increased. There is also some evidence of accumulation of glycosaminoglycans in the brain. The clinical symptoms, the complete deficiency of acidic beta-D-galactosidase and the storage products in visceral organs all suggest that this is a case of feline GM1-type gangliosidosis comparable with the severe infantile (Type 1) form of the disease in humans.

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Section: Discussionsupporting

confidence: 62%

“…analysis, composition analysis by g.l.c. and on the results of other studies on canine (Warner & O'Brien, 1982) and feline GM, gangliosidosis (Holmes & O'Brien, 1978b) the structures shown in Fig. 4 are proposed for the main oligosaccharide storage products (1), (2) (3) and (4) and the minor components associated with product (1).…”

Section: Vol 235mentioning

confidence: 64%

GM1 gangliosidosis (type 1) in a cat

Barker¹,

Blakemore²,

Dell³

et al. 1986

Biochemical Journal

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“…1), a number of previous studies have shown the accumulation of free glycan metabolites resulting from GLB1 deficiency. Many of these earlier studies relied on thin layer chromatography (TLC), capillary electrophoresis, or liquid chromatography to detect these species and for subsequent biochemical analysis for structural characterization [[3], [4], [5], [6],11,12,14,16,18]. Using these methods, most of these soluble glycans were shown to be metabolites of N-linked glycans originating from glycoproteins.…”

Section: Resultsmentioning

confidence: 99%

“…While commonly regarded as a gangliosidoses type LSD, β-galactosidase deficiency more accurately should be considered a broad spectrum oligosaccharidoses since, in addition to glycolipids, a substantial number of soluble N-linked glycans also accumulate in GM1 gangliosidosis. These disease-related oligosaccharides were detected in both affected tissues such as brain [3] and liver [[4], [5], [6]] as well as in biological fluids such as urine [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]] and amniotic fluid [17,19]. The discovery of these additional storage metabolites is consistent with the role of β-galactosidase in removing β-linked galactose from the NRE of oligosaccharides moieties found not only in gangliosides but in other glycoconjugates such as glycoproteins and keratan sulfate proteoglycans (Fig.…”

Section: Introductionmentioning

confidence: 99%

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Lawrence

Vleet

Mangini

et al. 2019

Molecular Genetics and Metabolism Reports

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IntroductionGM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids.ObjectiveIn this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover.ResultsUsing tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well.ConclusionsOur studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.

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“…The hepatocellular cytoplasmic vacuolation seen in the cats described in this paper appears to contain non-lipid material (as judged by light and electron microscopy) although hepatic levels of a 4MU-8 gal activity are lowered and the GM1 content is increased. The hepatocellular storage product in feline GM1 gangliosidosis is a large molecular weight glycopeptide with non-reducing galactose in p-D linkage (Holmes & O'Brien, 1978b).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Beta Galactosidase and Feline Gmi Gangliosidosis

Barnes¹,

Kelly

Pennock³

et al. 1981

Neuropathology Appl Neurobio

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This paper describes the clinical, morphological and biochemical features of three cats with a progressive neurological disorder. Clinical features were ataxia and progressive tremor. The morphological characteristics were those of lysosomal storage disease affecting neurones of the central nervous system and autonomic ganglia; membranous cytoplasmic bodies were demonstrated by electron microscopy in cerebral neurones. Chemical analysis of brain from two of the cats revealed an increased content of total gangliosides, sialic acid and a specific increase in GMI ganglioside. Enzyme analysis of homogenates of leucocytes, spleen and brain showed less than 5% or normal 4-methylumbelliferyl-beta galactosidase (4MU-beta gal) activity. In liver, activity was markedly reduced at pH values below 4.2, but there was considerable activity above this value. The properties of 4MU-beta gal in normal and diseased feline livers were investigated. Sephadex gel filtration of diseased liver homogenates showed an absence of two thermolabile "acid' components, and reduced activity of a third thermostable "neutral' component. The biochemical abnormalities found in the diseased cats are similar to those found in human juvenile GMI gangliosidosis (type 2).

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Hepatic storage of oligosaccharides and glycolipids in a cat affected with GM1 gangliosidosis

Cited by 15 publications

References 31 publications

GM1 gangliosidosis (type 1) in a cat

GM1 gangliosidosis (type 1) in a cat

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Hepatic Beta Galactosidase and Feline Gmi Gangliosidosis

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