Consequences of beta-glucocerebrosidase deficiency in epidermis. Ultrastructure and permeability barrier alterations in Gaucher disease.

Abstract

Hydrolysis of glucosylceramide by j-glucocerebrosidase results in ceramide, a critical component of the intercellular lamellae that mediate the epidermal permeability barrier. A subset of type 2 Gaucher patients displays ichthyosiform skin abnormalities, as do transgenic Gaucher mice homozygous for a null allele. To investigate the relationship between glucocerebrosidase deficiency and epidermal permeability barrier function, we compared the stratum corneum (SC) ultrastructure, lipid content, and barrier function of Gaucher mice to carrier and normal mice, and to hairless mice treated topically with bromoconduritol B epoxide (BrCBE), an irreversible inhibitor of glucocerebrosidase. Both Gaucher mice and BrCBE-treated mice revealed abnormal, incompletely processed, lamellar body-derived sheets throughout the SC interstices, while transgenic carrier mice displayed normal bilayers. The SC of a severely affected type 2 Gaucher's disease infant revealed similarly abnormal ultrastructure. Furthermore, the Gaucher mice demonstrated markedly elevated transepidermal water loss (4.2±0.6 vs < 0.10 g/m2 per h). The electron-dense tracer, colloidal lanthanum, percolated between the incompletely processed lamellar body-derived sheets in the SC interstices of Gaucher mice only, demonstrating altered permeability barrier function. Gaucher and BrCBE-treated mice showed < 1% and < 5% of normal epidermal glucocerebrosidase activity, respectively, and the epidermis/SC of Gaucher mice demonstrated elevated glucosylceramide (5-to 10-fold), with diminished ceramide content. Thus, the skin changes observed in Gaucher mice and infants may result from the formation of incompetent intercellular lamellar bilayers due to a decreased hydrolysis of glucosylceramide to ceramide. Glucocerebrosidase therefore appears necessary for the generation of membranes of sufficient functional competence for epidermal barrier function. (J.

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

“…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.…”

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

“…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]. These RecNci I point mutation mice exhibit severe ichthyosiform skin abnormalities presumably caused by accumulation of epidermal GlcCers together with decreased levels of Cers [7], as also shown for L-GlcCerase knockout (null allele) mice by Holleran et al [6].…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…157,158 In recent years, it has become evident that this most critical SC functionethe permeability barriereis impaired in most ichthyosis forms. 11,60,[159][160][161][162][163][164] Several murine knockout models for ichthyosis [Spink5 (e/e), Tgm1 (e/e), Abca12 (e/e) mice, [165][166][167] Alox12b (e/e), 168 Cldn1(e/e) 169 ] have demonstrated neonatal lethality as a result of dehydration, underscoring the critical role of these genes in permeability barrier competence. Mutations that either alter the lipid composition of the SC membranesedisorders of lipid metabolismeor affect the function of the corneocyte structural proteinsedisorders of keratinocyte proteinseresult in increased water movement through the intercellular pathway.…”

“…7 The combination of all alterations observed with this technique may be diagnostic for many forms of ichthyosis. 8 Most importantly, the ultrastructural demonstration of disturbances of lipid metabolism gives valuable insights into the pathophysiologic basis of many ichthyoses 11,60,[159][160][161][162][163][164] and enables a function-driven approach. 7,8,11 Histopathology, immunochemistry, and other nongenetic analyses Routine histopathological findings in most ichthyoses are nondiagnostic, often demonstrating only epidermal hyperplasia and varying degrees of orthohyperkeratosis.…”