Decreased ganglioside neuraminidase activity in fibroblasts from mucopolysaccharidosis patients Inhibition of the activity in vitro by sulfated glycosaminoglycans and other compounds

Baumkötter, J.; Cantz, Michael

doi:10.1016/0304-4165(83)90225-8

Cited by 35 publications

(20 citation statements)

References 20 publications

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“…Similar results were reported in another study showing that 21 different lysosomal enzyme activities in leukocytes were strongly inhibited by mixing them in vitro with various GAGs, with the mechanism again believed to be possibly secondary to GAG-enzyme binding [100]. A third study showed that neuraminidase activities toward GD1a, GD3 and GM3 were diminished in fibroblasts of MPS diseases, possibly due to binding of sulfated GAGs with the enzyme [101]. While a plausible mechanism for disrupting ganglioside degradation, it is not readily apparent why different MPS disorders with different types of GAG storage each result in storage of essentially the same pattern of gangliosides.…”

Section: Mechanisms and Consequences Of Secondary Storagesupporting

confidence: 77%

Secondary lipid accumulation in lysosomal disease

Walkley¹,

Vanier²

2009

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

194

181

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Lysosomal diseases are inherited metabolic disorders caused by defects in a wide spectrum of lysosomal and a few non-lysosomal proteins. In most cases a single type of primary storage material is identified, which has been used to name and classify the disorders: hence the terms sphingolipidoses, gangliosidoses, mucopolysaccharidoses, glycoproteinoses, and so forth. In addition to this primary storage, however, a host of secondary storage products can also be identified, more often than not having no direct link to the primary protein defect. Lipids - glycosphingolipids and phospholipids, as well as cholesterol - are the most ubiquitous and best studied of these secondary storage materials. While in the past typically considered nonspecific and nonconsequential features of these diseases, newer studies suggest direct links between secondary storage and disease pathogenesis and support the view that understanding all aspects of this sequestration process will provide important insights into the cell biology and treatment of lysosomal disease.

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Section: Mechanisms and Consequences Of Secondary Storagesupporting

confidence: 77%

Secondary lipid accumulation in lysosomal disease

Walkley¹,

Vanier²

2009

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

194

181

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“…However, the accumulation of lipid-like material, possibly G M2 and G M3 gangliosides, did appear in the cortical cells of these mice by 18 wk of age, although the extent was minimal compared with that observed in 14-wk-old untreated MPS IIIA mice. The gangliosides may be secondarily stored as a result of glycosaminoglycan interference with ganglioside catabolism (35,36). It has been proposed that ganglioside accumulation is the possible cause of neurologic deficits observed in LSDs that secondarily store these compounds (37).…”

Section: Discussionmentioning

confidence: 99%

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Gliddon

Hopwood

2004

Pediatr Res

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Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome) is a lysosomal storage disorder characterized by severe CNS degeneration, resulting in behavioral abnormalities and loss of learned abilities. Early treatment is vital to prevent long-term clinical pathology in lysosomal storage disorders. We have used naturally occurring MPS IIIA mice to assess the effects of long-term enzyme-replacement therapy initiated either at birth or at 6 wk of age. MPS IIIA and normal control mice received weekly i.v. injections of 1 mg/kg recombinant human sulfamidase until 20 wk of age. Sulfamidase is able to enter the brain until the blood-brain barrier completely closes at 10 -14 d of age. MPS IIIA mice that were treated from birth demonstrated normal weight, behavioral characteristics, and ability to learn. MPS IIIA mice that were treated from birth performed significantly better in the Morris water maze than MPS IIIA mice that were treated from 6 wk of age or left untreated. A reduction in storage vacuoles in cells of the CNS in MPS IIIA mice that were treated from birth is consistent with the improvements observed. These data suggest that enzyme that enters the brain in the first few weeks of life, before the blood-brain barrier matures, is able to delay the development of behavior and learning difficulties in MPS IIIA mice. , and glucosamine-6-sulfatase (MPS IIID) (1). MPS III has an estimated incidence of 1 in 66,000 births in Australia, with MPS IIIA the most common (2). MPS III is characterized by severe CNS degeneration, resulting in progressive mental retardation. After a period of seemingly normal development, patients exhibit a range of symptoms, including rapid loss of social skills with hyperactivity and aggressive behavior, loss of learning ability, disturbed sleep patterns, hirsutism, coarse facies, and diarrhea. Death occurs in severely affected children in the mid-to late-teenage years usually as a result of respiratory infection (3). Phenotypic variation in MPS III ranges from severe to intermediate to attenuated, a result of heterogeneity at the molecular level. A total of 62 causative mutations have been identified for MPS IIIA (4).A naturally occurring mouse model of MPS IIIA has been described (5), a colony of which is established in Adelaide. Disease in the mice results from a base substitution at codon 31 in the sulfamidase gene, altering an aspartic acid to an asparagine (D31N) (6). This aspartic 31 is involved in binding of the divalent metal ion needed for catalytic function (7-9). MPS IIIA mice exhibit widespread intracellular storage in a variety of cell types. Affected mice are also reported to store secondarily gangliosides G M2 and G M3 , a feature also reported in two MPS IIIA dog models (10,11), a knock-out MPS IIIB mouse (12), and a caprine MPS IIID model (13

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“…filippo Fibroblasts-Secondary storage of glycoconjugates such as gangliosides in Sanfilippo occurs, at least in part, due to the inhibition of lysosomal hydrolases by accumulating heparan sulfate (9,11). To determine whether heparan sulfate storage causes the secondary storage of additional glycoconjugates, we assayed the amount of chondroitin and dermatan sulfate as a mixture and heparan sulfate by mass spectrometry of the enzymatically released disaccharides.…”

Section: Secondary Storage Of Chondroitin/dermatan Sulfate In San-mentioning

confidence: 99%

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Lamanna

Lawrence

Sarrazin

et al. 2011

Journal of Biological Chemistry

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Mucopolysaccharidoses are a group of genetically inherited disorders that result from the defective activity of lysosomal enzymes involved in glycosaminoglycan catabolism, causing their intralysosomal accumulation. Sanfilippo disease describes a subset of mucopolysaccharidoses resulting from defects in heparan sulfate catabolism. Sanfilippo disorders cause severe neuropathology in affected children. The reason for such extensive central nervous system dysfunction is unresolved, but it may be associated with the secondary accumulation of metabolites such as gangliosides. In this article, we describe the accumulation of dermatan sulfate as a novel secondary metabolite in Sanfilippo. Based on chondroitinase ABC digestion, chondroitin/dermatan sulfate levels in fibroblasts from Sanfilippo patients were elevated 2-5-fold above wild-type dermal fibroblasts. Lysosomal turnover of chondroitin/dermatan sulfate in these cell lines was significantly impaired but could be normalized by reducing heparan sulfate storage using enzyme replacement therapy. Examination of chondroitin/dermatan sulfate catabolic enzymes showed that heparan sulfate and heparin can inhibit iduronate 2-sulfatase. Analysis of the chondroitin/dermatan sulfate fraction by chondroitinase ACII digestion showed dermatan sulfate storage, consistent with inhibition of iduronate 2-sulfatase. The discovery of a novel storage metabolite in Sanfilippo patients may have important implications for diagnosis and understanding disease pathology.

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Decreased ganglioside neuraminidase activity in fibroblasts from mucopolysaccharidosis patients Inhibition of the activity in vitro by sulfated glycosaminoglycans and other compounds

Cited by 35 publications

References 20 publications

Secondary lipid accumulation in lysosomal disease

Secondary lipid accumulation in lysosomal disease

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

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