Gaucher Disease in the Neonate: A Distinct Gaucher Phenotype Is Analogous to a Mouse Model Created by Targeted Disruption of the Glucocerebrosidase Gene

Sidransky, Ellen; Sherer, David M.; Ginns, Edward I.

doi:10.1203/00006450-199210000-00023

Cited by 139 publications

(89 citation statements)

References 10 publications

(12 reference statements)

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“…However, all symptoms cannot be fully explained by this axis. For example, the neonatal lethality of GBA1 −/− mice, which is mainly because of a keratinocyte disorder (68,69), was not rescued on a Mincle-deficient background. Additionally, FLderived GM-CSF myeloid cells from GBA1 −/− mice displayed an enlarged cell size much like Gaucher cells, and this was observed regardless of Mincle expression.…”

Section: Discussionmentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

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

138

126

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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

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Section: Discussionmentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

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

138

126

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“…Among three distinct clinical types of Gaucher disease, type 2 (acute neuronopathic) is the most fatal form [10]. Complete loss of L-GlcCerase activity in some cases of type 2 Gaucher disease is fatal within a few days after birth and is accompanied with a severe ichthyosiform dermatosis (collodion baby phenotype) [8,9]. Recently, a mouse model for this disease has been created by introducing point mutations into the murine gene encoding L-GlcCerase resulting in an almost complete loss of enzyme activity [7].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of protein‐bound epidermal glucosylceramides in β‐glucocerebrosidase deficient type 2 Gaucher mice

1999

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The epidermal permeability barrier for water is essentially maintained by extracellular lipid membranes within the interstices of the stratum corneum. Ceramides, the main components of these membranes, derive in large part from hydrolysis of glucosylceramides mediated by the lysosomal enzyme L L-glucocerebrosidase. As analyzed in this work, the L Lglucocerebrosidase deficiency in type 2 Gaucher mice (RecNci I) resulted in an accumulation of all epidermal glucosylceramide species accompanied with a decrease of the related ceramides. However, the levels of one ceramide subtype, which possesses an K K-hydroxypalmitic acid, was not altered in RecNci I mice suggesting that the L L-glucocerebrosidase pathway is not required for targeting of this lipid to interstices of the stratum corneum. Most importantly, g g-hydroxylated glucosylceramides which are protein-bound to the epidermal cornified cell envelope of the transgenic mice accumulated up to 35-fold whereas levels of related protein-bound ceramides and fatty acids were decreased to 10% of normal control. These data support the hypothesis that in wild-type epidermis g g-hydroxylated glucosylceramides are first transferred enzymatically from their linoleic esters to proteins of the epidermal cornified cell envelope and then catabolized to protein-bound ceramides and fatty acids, thus contributing at least in part to the formation of the lipid-bound envelope.z 1999 Federation of European Biochemical Societies.

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“…The hypothesis presented helps in understanding many symptoms of the GD phenotype that cannot be explained by the mere presence of GCs; first of all the discrepancy between the severe symptomatology and organ damage especially in perinatal-lethal devastating variants of GD (Mignot et al 2003;Sidransky et al 1992) and in the mouse model of GD created by targeted disruption of GlcCer-ase gene (Tybulewicz et al 1992), characterized by profound GlcCerase deficiency.…”

Section: Glucosylceramide Transfermentioning

confidence: 99%

“…It is likely to play a role in the serious skin symptomatology seen in perinatal GD, described as 'collodion baby' (Lipson et al 1991) or ichthyosis (Sherer et al 1993), which is currently explained as being caused by a decrease in ceramide normally released from GlcCer in the terminal part of epidermis by GlcCer-ase. The altered ratio of GlcCer to ceramides leads to an alteration of the hydrophobic barrier, decreased keratinocyte desquamation (Eblan et al 2005;Holleran et al 1994;Sidransky et al 1992) and their increased proliferation (Marsh et al 1995). Further, the myocardial involvement observed in GD (Platzker et al 1985;Torloni et al 2002) has been explained solely by the infiltration of the heart by GCs (Edwards et al 1983;Smith et al 1978), while the syndrome of pulmonary hypertension is thought to be caused by GCs occupying the lumina of the alveolar capillaries or alveoli (Mistry et al 2002), although this syndrome has been described in the absence pulmonary GCs (Theise and Ursell 1990).…”

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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Gaucher Disease in the Neonate: A Distinct Gaucher Phenotype Is Analogous to a Mouse Model Created by Targeted Disruption of the Glucocerebrosidase Gene

Cited by 139 publications

References 10 publications

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Accumulation of protein‐bound epidermal glucosylceramides in β‐glucocerebrosidase deficient type 2 Gaucher mice

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

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