Reduced cerebral vascularization in experimental neuronopathic Gaucher disease

Abstract

The glycosphingolipidosis, Gaucher disease, in which a range of neurological manifestations occur, results from a deficiency of acid -glucocerebrosidase, with subsequent accumulation of -glucocerebroside, its upstream substrates, and the non-acylated congener -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 -glucosylsphingosine. Further in vitro studies confirmed a concentration-dependent impairment of endothelial cytokinesis upon exposure to quasi-pathological concentrations of -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.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…Thirty non-randomized clinical trials and observational studies with full-study reporting were assessed using the Newcastle–Ottawa scoring tool [ 3 , 26 , 33 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], of which 19 were deemed to have a high risk of bias (score 0–3; Table S2 ). Thirty-two animal studies were assessed using the SYRCLE risk of bias tool [ 45 , 53 , 58 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ,…”

“…Of the 74 articles included, 56 articles pertained to lyso-Gb1 and GD pathology. They encompassed (in a non-mutually exclusive manner) ten clinical (autopsy) studies [ 54 , 55 , 56 , 57 , 58 , 59 , 61 , 62 , 63 , 93 ] and 48 studies reporting preclinical data (19 studies reporting in vitro data and 32 studies reporting in vivo data) [ 26 , 45 , 53 , 58 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ,…”

“…Lyso-Gb1 accumulation was observed in the brain [ 53 , 65 , 67 , 68 , 69 , 70 , 72 , 73 , 76 , 82 , 83 , 84 , 85 , 86 , 88 , 89 , 90 , 91 , 111 ], viscera [ 65 , 73 , 86 , 91 ], and blood [ 111 ], but not bone, and in a wide range of neuronopathic GD murine models and one ovine model. Although murine models are highly economical, lamb brain is considered more translationally relevant to the human brain as both are gyrencephalic and have similar anatomy and physiological vital signs.…”

“…A wide range of in vitro experiments has also demonstrated that lyso-Gb1 is cytotoxic to some cell types and pro-inflammatory in others, is damaging to specific neurons, impairs cell fission during cytokinesis, and interferes with osteoblasts, immune regulation, and signal transduction ( Table 2 ). Exogenous lyso-Gb1 induced hemolysis and was cytotoxic towards cultured human cholinergic neurons, human umbilical vein endothelial cells, and 3T3 and PC12 cell lines [ 64 , 83 , 100 , 107 ]. Lyso-Gb1 toxicity towards fibroblasts and neural crest-derived neoplastic cells in vitro occurred at a similar concentration to that which it accumulates in vivo [ 64 ].…”

Glucocerebrosidase: Functions in and Beyond the Lysosome

“…The same lipids were proposed to activate the complement cascade activation and associated local tissue inflammation [173]. GlcSph is hypothesized to diminished cerebral microvascular density in mice, based on the observed interference of the lipid with endothelial cytokinesis [174]. Earlier studies have provided evidence that GlcSph promotes lysis of red blood cells, impairs cell fission during cytokinesis, damages specific neurons, interferes with growth, and activates pro-inflammatory phospholipase A2 (see for a review [91]).…”