Reduced cerebral vascularization in experimental neuronopathic Gaucher disease. Issue 1 (14th December 2017)

• Record Type: Journal Article
• Authors: Smith, Nicholas JC; Fuller, Maria; Saville, Jennifer T; Cox, Timothy M
• Is Part Of: Journal of pathology. Volume 244:Issue 1(2018)
• Page Start: 120
• Page End: 128
• Publication Date: 2017-12-14
• Subjects: Gaucher -- angiogenesis -- β‐glucosylsphingosine -- actin; Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4992
• Languages: English
• ISSNs: 0022-3417

Abstract

Abstract: The glycosphingolipidosis, Gaucher disease, in which a range of neurological manifestations occur, results from a deficiency of acid β‐glucocerebrosidase, with subsequent accumulation of β‐glucocerebroside, its upstream substrates, and the non‐acylated congener β‐glucosylsphingosine. However, the mechanisms by which end‐organ dysfunction arise are poorly understood. Here, we report strikingly diminished cerebral microvascular density in a murine model of disease, and provide a detailed analysis of the accompanying cerebral glycosphingolipidome in these animals, with marked elevations of β‐glucosylsphingosine. Further in vitro studies confirmed a concentration‐dependent impairment of endothelial cytokinesis upon exposure to quasi‐pathological concentrations of β‐glucosylsphingosine. These findings support a premise for pathogenic disruption of cerebral angiogenesis as an end‐organ effect, with potential for therapeutic modulation in neuronopathic Gaucher disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.