Endothelial cell dysfunction in globoid cell leukodystrophy


  • SIGNIFICANCE: This Mini-Review summarizes recent advances implicating endothelial cell dysfunctions resulting from lysosomal β-galactosylceramidase deficiency in globoid cell leukodystrophy (GLD). Microvascular alterations occur in the central nervous system and peripheral tissues of affected patients and twitcher mice, an animal model of the disease. These alterations may depend, at least in part, on the local and systemic angiostatic activity of the neurotoxic metabolite psychosine, with endothelial dysfunction representing a novel pathogenic mechanism of this neurodegenerative disorder. Understanding the molecular mechanisms responsible for the psychosine-dependent and psychosine-independent microvascular alterations may pave the way toward more efficacious therapeutic approaches in GLD.


Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Microvascular alterations have been observed in various neurodegenerative disorders, including genetic leukodystrophies. Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by β-galactosylceramidase (GALC) deficiency and characterized by the accumulation of the neurotoxic metabolite psychosine in the central nervous system and peripheral tissues. Structural and functional alterations occur in the microvascular endothelium of the brain of GLD patients and twitcher mice, a murine model of the disease. In addition, increased vessel permeability and a reduced capacity to respond to proangiogenic stimuli characterize the endothelium of twitcher animals. On the one hand, these alterations may depend, at least in part, on the local and systemic angiostatic activity exerted by psychosine on endothelial cells. On the other hand, studies performed in vivo on zebrafish embryos and in vitro on human endothelial cells suggest that GALC downregulation may also lead to psychosine-independent neuronal and vascular defects. Together, experimental observations indicate that endothelial cell dysfunctions may represent a novel pathogenic mechanism in human leukodystrophies, including GLD. A better understanding of the molecular mechanisms responsible for these microvascular alterations may provide new insights for the therapy of GLD. © 2016 Wiley Periodicals, Inc.