Inhibition of angiogenesis by β-galactosylceramidase deficiency in globoid cell leukodystrophy

Mirella Belleri, Roberto Ronca, Daniela Coltrini, Beatrice Nico, Domenico Ribatti, Pietro L. Poliani, Arianna Giacomini, Patrizia Alessi, Sergio Marchesini, Marta B. Santos, Ernesto R. Bongarzone, Marco Presta

Research output: Contribution to journalArticlepeer-review

Abstract

Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme β-galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post-natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine β-galactosylceramidase complementary DNA. Finally, RNA interference-mediated β-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that β-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy.

Original languageEnglish
Pages (from-to)2859-2875
Number of pages17
JournalBrain
Volume136
Issue number9
DOIs
Publication statusPublished - 2013

Keywords

  • angiogenesis
  • Krabbe disease
  • neurodegeneration
  • psychosine
  • twitcher mice

ASJC Scopus subject areas

  • Clinical Neurology

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