Reduced cerebral vascularization in experimental neuronopathic Gaucher disease.


Type
Article
Change log
Authors
Fuller, Maria 
Saville, Jennifer T 
Cox, Timothy M 
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.

Description
Keywords
Gaucher, actin, angiogenesis, β-glucosylsphingosine, Animals, Brain, Disease Models, Animal, Gaucher Disease, Humans, Mice, Microvessels, Neovascularization, Pathologic, Psychosine
Journal Title
J Pathol
Conference Name
Journal ISSN
0022-3417
1096-9896
Volume Title
244
Publisher
Wiley