Sphingolipid hydrolases in brain tissue of patients with generalized gangliodosis

Brady, Roscoe O.; O’Brien, John S.; Bradley, Roy M.; Gal, Andrew E.

doi:10.1016/0005-2760(70)90079-2

Cited by 45 publications

(7 citation statements)

References 12 publications

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“…Thus the mutation in Krabbe's disease, which gives rise to a deficiency of galactocerebroside (3-galactosidase (Suzuki & Suzuki 1970) is not allelic with the GM, gangliosidosis mutation. Previous results showed that galactocerebroside fi-galactosidase activities are not deficient in GM, gangliosidosis (Brady et al 1970, Suzuki & Suzuki 1970) and that B-galactosidase A activities (measured with synthetic substrates) are not deficient in Krabbe's disease , pointing to the same conclusion.…”

Section: Properties Of Gm1 /I-galactosidases and Other /I-galactosidasesmentioning

confidence: 79%

Molecular genetics of GM₁β‐galactosidase

O’Brien

1975

Clinical Genetics

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The molecular genetics of GM1β‐galactosidase is reviewed. This enzyme exists in two forms, A and B. Form A is monomeric with a molecular weight of 72,000 and appears to be coded by a single autosomal locus. Form B is polymeric and cross‐reacts with anti‐A antibodies; it is coded wholly or in part by the same locus that codes for A. The simultaneous loss of A and B in GM1 gangliosidosis is explained. None of the other β‐galactosidases, including neutral β‐galactosidase, ceramide lactoside β‐galactosidase or cerebroside β‐galactosidase cross‐react with anti‐A antibodies, demonstrating that they are coded by loci separate from A. GM1, β‐galactosidase A is heterocatalytic, cleaving β‐Dgalactose from ganglioside GM1, lactose, N‐acetyllactosamine, and galactose‐containing glycoproteins such as asialofetuin, red cell stromal glycoproteins and keratan sulfate. The pleotropic effects of a single mutation affecting the locus for β‐galactosidase A can be explained by a one gene: one polypeptide: many substrates model. Phenotypic variability among β‐galactosidase A mutants may result from better residual activity of the mutant enzyme for one substrate than for another. Patients with normal intelligence and severe bony deformities, who are homozygous for a mutation affecting the enzyme, illustrate this point. Thus far all human mutants for GM1, β‐galactosidase studied are structural mutants, synthesizing nearly normal quantities of mutant enzyme; one is a proven Km mutant, the others are very likely so.

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Section: Properties Of Gm1 /I-galactosidases and Other /I-galactosidasesmentioning

confidence: 79%

Molecular genetics of GM₁β‐galactosidase

O’Brien

1975

Clinical Genetics

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“…This could explain the increased activity of iduronate sulfatase found in the brain and liver of the young rats. Increased activity of lysosomal enzymes other than the deficient one has been seen in the tissues of patients with MPS (24), generalized gangliosidosis (25), and many other lysosomal diseases, and in rat liver and spleen of animals injected with phenylhydrazine and human erythrocyte stroma (26). This presumably occurs via the redundant stimulation by the accumulated substrate of new enzyme synthesis in a nonspecific way (27).…”

Section: Discussionmentioning

confidence: 99%

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Constantopoulos¹,

Rees²,

Cragg³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACGIntracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration of suramin, 500 mg/kg, to 2-month-old rats causes a 5-to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excretion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 Ag of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside Gm2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, f-glucuronidase, and hyaluronidase in the liver of the suramintreated mature rats were consistently decreased, whereas those of a-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 pM or hi er. The activity of -glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncom titive.-The suramin-treated rat may be a useful experimentaFanimal model of mucopolysaccharidosis.Mucopolysaccharidoses (MPS) are diseases caused by the heritable deficiency of lysosomal enzymes necessary for the degradation of glycosaminoglycans (GAG) (1, 2). The genetic defect results in tissue storage and excessive urinary excretion of various partially degraded GAG. In addition, most of these disorders are characterized by sphingolipid abnormalities, particularly of the brain (3). Recently, one of us found that intracerebral injection of the trypanocidal drug suramin resulted in the formation of membranous neuronal and neuroglial inclusions (4). It was suggested that these inclusion bodies may consist of glycolipids and GAG and that the experiment indicated a possible experimental model for storage diseases. The present study was conducted to examine biochemical alterations in the liver and in the brain of rats after intravenous and intracerebral injection of suramin. The pathologic changes found are similar to those detected in the genetic MPS (5) and suggest that the administration of suramin to rats may provide a useful model for the study of the pathogenesis of these diseases. A preliminary report of this work has been published(6). Table 1. Three groups of confrol rats received 0.5 ml of saline. Multiple intracerebral injections of suramin, totaling 40-250 ,ug in 10 ,l of saline (i.e., 4-25 ,ug/,ul) were given to 10-day-old and to 2-month-old rats. Control rats were given 10 ,l of saline. The rats were sacrificed between 7 and 10 days after injection. The livers were removed, weighed, and frozen in liquid nitrogen. Rats receiving intracerebral injections were sacrificed after 2-5 days. The regions of brain about 4 mm in diameter surr...

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“…5 and 6) to high in neurons in NPC (Figs. 7,8,9). The remarkable heterogeneity in neurons in NPC suggests a loose association of LacCer with the disorder under the same loss of NPC1 sterol/glycolipid sensing protein function [12].…”

Section: Lsds Associated With Increased Laccermentioning

confidence: 94%

“…For instance, in MPS I-III (the group deficient in heparan sulphatedegrading enzymes) activity of β-galactosidase is inversely proportional to the degree of storage [73]. However, in GM1 gangliosidosis, which is inherently deficient in one of the critical LacCer-degrading enzymes, the increase in LacCer in the cerebral grey matter (see above) is associated with its normal or even increased degradation rate [8]. In contrast to our finding of a significant increase in LacCer in GSD II (Table 2), β-galactosidase activity has been found to be increased in this disorder [28].…”

Section: Significance Of Laccer Levels In Lsdsmentioning

confidence: 99%

Lactosylceramide in lysosomal storage disorders. A comparative immunohistochemical and biochemical study

et al. 2005

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Immunohistochemical studies of the presence of lactosylceramide (LacCer) in lysosomal storage disorders (LSDs) were done using anti-LacCer monoclonal antibody of the CDw 17 type (clone MG-2). No sign of an association between LacCer and the lysosomal system in normal cells was observed, except for histiocytes active in phagocytosis. A comparative study of a group of LSDs showed a general tendency for LacCer to increase in storage cells in Niemann-Pick disease type C (NPC), and types A and B, GM1 gangliosidosis, acid lipase deficiency, glycogen storage disease type II and mucopolysaccharidoses. LacCer accumulated in storage cells despite normal activity of relevant lysosomal degrading enzymes. The accumulation of LacCer displayed variability within storage cell populations, and was mostly expressed in neurons in NPC. An absence of the increase in LacCer in storage cells above control levels was seen in neuronal ceroid lipofuscinoses (neurons and cardiocytes) and in Fabry disease. Gaucher and Krabbe cells showed significantly lower levels, or even the absence, of LacCer compared with control macrophages. Results of immunohistochemistry were corroborated by semiquantitative lipid thin-layer chromatography (TLC). It is suggested that different associations of LacCer with the lysosomal storage process may reflect differences in glycosphingolipid turnover induced by the storage-compromised lysosomal/endosomal system.

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Sphingolipid hydrolases in brain tissue of patients with generalized gangliodosis

Cited by 45 publications

References 12 publications

Molecular genetics of GM₁β‐galactosidase

Molecular genetics of GM₁β‐galactosidase

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Lactosylceramide in lysosomal storage disorders. A comparative immunohistochemical and biochemical study

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Sphingolipid hydrolases in brain tissue of patients with generalized gangliodosis

Cited by 45 publications

References 12 publications

Molecular genetics of GM1β‐galactosidase

Molecular genetics of GM1β‐galactosidase

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Lactosylceramide in lysosomal storage disorders. A comparative immunohistochemical and biochemical study

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Molecular genetics of GM₁β‐galactosidase

Molecular genetics of GM₁β‐galactosidase