Endothelial cell dysfunction in globoid cell leukodystrophy

Abstract

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.

Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

“…These findings represent an alternative to older theories of the dying-forward and demyelination-dependent progression for KD 7 , based on the analysis of peripheral nerves ultrastructure 10, 20 . Additionally, the affection of endothelial cells-especially blood vessel walls architecture-in KD mice 21, 22 further suggests that therapeutic approaches based only on the rescue of GALC activity in the brain may not be sufficient to cure KD disease.…”

Reduced cerebral vascularization in experimental neuronopathic Gaucher disease

“…Here, we report a marked reduction in cerebral microvasculature L vd in a murine model of neuronopathic Gaucher disease. The determinations represent total vessel length per cubic micrometre of tissue, and avoid technical bias introduced by the use of differing reference volumes . Although differences in vascular perfusion and luminal patency must be considered, the observed trend in vascular volume proved to be consistent in all the mutant diseased mice studied.…”

Biochemical, cell biological, pathological, and therapeutic aspects ofKrabbe's disease

“…Alterations of brain microvasculatures and disruption of the blood–brain barrier (BBB) are critical features of many neurological disorders (Greenberg and Jin, ; Segura et al, ; Rosenberg, ; Belleri and Presta, ). The abnormalities in brain microvasculature in KD were initially reported by Kondo and Suzuki () and reported later by other research groups (Belleri et al, ; Giacomini et al, ; Belleri and Presta, ).…”

“…Alterations of brain microvasculatures and disruption of the blood-brain barrier (BBB) are critical features of many neurological disorders (Greenberg and Jin, 2005;Segura et al, 2009;Rosenberg, 2012;Belleri and Presta, 2016). The abnormalities in brain microvasculature in KD were initially reported by Kondo and Suzuki (1993) and reported later by other research groups (Belleri et al, 2013;Giacomini et al, 2015;Belleri and Presta, 2016). Key features of the microvasculature abnormalities in the brains of KD patients or twi mice include enlargement of perivascular space, increased brain vascular permeability, macrophage andinfiltration, decreased microvessel density, reduced vessel length, increased vessel fragmentation, dilated lumens with altered endothelium morphology, and discontinuous endothelial wrapping by smooth muscle cells (Kondo and Suzuki, 1993;Belleri et al, 2013;Giacomini et al, 2015).…”