Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype

Orvisky, Eduard; Park, Joseph K.; LaMarca, Mary E.; Ginns, Edward I.; Martin, Brian M.; Tayebi, Nahid; Sidransky, Ellen

doi:10.1016/s1096-7192(02)00117-8

Cited by 172 publications

(147 citation statements)

References 30 publications

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“…However, various deacylated glycosphingolipids have been identified in lysosomal glycolipid storage diseases (see discussion in ref. 18 for an overview). For example, in Gaucher disease, glucosylsphingosine, the deacylated form of the accumulating glucosylceramide, is known to be increased as well (18,19).…”

Section: Resultsmentioning

confidence: 99%

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Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Aerts

Groener

Kuiper

et al. 2008

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

626

565

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Fabry disease is an X-linked lysosomal storage disease caused by deficiency of ␣-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of ␣-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.

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Section: Resultsmentioning

confidence: 99%

“…18 for an overview). For example, in Gaucher disease, glucosylsphingosine, the deacylated form of the accumulating glucosylceramide, is known to be increased as well (18,19). The same holds for Krabbe disease in which galactosylsphingosine or psychosine (deacylated galactosylceramide) is ele-vated (20)(21)(22)(23).…”

Section: Resultsmentioning

confidence: 99%

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Aerts

Groener

Kuiper

et al. 2008

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

626

565

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“…This compound with wellrecognized toxicity (reviewed by Orvisky et al 2002), present in normal tissues in trace amounts, can increase several hundred-fold in various tissues in GD (Nilsson et al 1982;Orvisky et al 2000Orvisky et al , 2002. Its accumulation is considered to be responsible for the devastating clinical course of patients with the infantile type of Gaucher disease (Orvisky et al 2000(Orvisky et al , 2002, especially for the neuronal damage (Schueler et al 2003).…”

Section: Glucosylceramide Transfermentioning

confidence: 99%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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SummaryGaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer‐ase) is characterized by deficient degradation of beta‐glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology—Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer‐based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non‐macrophage cells) the uncleaved GlcCer, in GlcCer‐ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long‐standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer‐ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.

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“…Glucosylsphingosine (Gsp) is increased in skin of patients with atopic dermatitis (Okamoto et al, 2003). Gsp, a metabolic precursor of glucocerebroside synthesis, also accumulates in the cerebral and cerebellar cortex in patients both with type 2 and 3 Gaucher disease (Nilsson and Svennerholm, 1982;Orvisky et al, 2002). Elevated levels of glucosylsphingosine were also seen in brains of Itch Scratch Responses Induced by Glucosylsphingosine 317 type 2 Gaucher mice (Orvisky et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Glucosylsphingosine Induces Itch-Scratch Responses in Mice

Kim¹,

Kim²,

Noh³

et al. 2010

Biomolecules and Therapeutics

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-Pruritus is one of major symptoms in atopic dermatis. The pathophysiological mechanism of pruritus is unclear. The search for pruritogen is important in elucidating the pathophysiological mechanism of pruritus in atopic dermatitis. Glucosylsphingosine (Gsp) is upregulated in the strateum corneum of atopic dermatitis patients. We investigated to determine whether Gsp induces itch-scratch responses (ISRs) in mice. Intradermal administration of Gsp induces ISRs. Gsp dose-dependently induced scratching response at 50-500 nmol/site range. Pretreatment with naltrexone, an opioid μ receptor antagonist, and capsaicin, a TrpV1 receptor agonist, inhibited Gsp-induced ISRs. Additionally, Gsp-induced ISRs were also suppressed by cyproheptadine, an antagonist of serotonin receptor. These findings suggest that Gsp-induced scratching might be at least partly mediated by capsaicin-sensitive primary afferents, and the opioids receptor systems might be involved in transmission of itch signaling in the central nervous system. Furthermore, our findings suggest that Gsp-induced ISRs may be attributable to the serotonin-mediated pathways and Gsp is not any more one of byproducts of abnormal skin barrier but can lead to induce pruritus, one of typical symptoms of atopic dermatitis.

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Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype

Cited by 172 publications

References 30 publications

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Glucosylsphingosine Induces Itch-Scratch Responses in Mice

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