The glycosphingolipidosis of 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.
PMID: 28981147 [PubMed - as supplied by publisher]