The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche

Article (PDF Available)inBlood 116(11):1857-66 · September 2010with29 Reads
DOI: 10.1182/blood-2009-12-256461 · Source: PubMed
Abstract
The balance between survival and death in many cell types is regulated by small changes in the intracellular content of bioactive sphingolipids. Enzymes that either produce or degrade these sphingolipids control this equilibrium. The findings here described indicate that the lysosomal galactocerebrosidase (GALC) enzyme, defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell (HSPC) niche by contributing to the control of the intracellular content of key sphingolipids. Indeed, we show that both insufficient and supraphysiologic GALC activity-by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model-induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect HSPC survival and function and the functionality of the stem cell niche. Therefore, GALC and, possibly, other enzymes for the maintenance of niche functionality and health tightly control the concentration of these sphingolipids within HSPCs.
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    • "For instance, GALC deficiency leads to a significant increase in the brain levels of the lipid raft component lactosylceramide (Tominaga et al., 2004), a molecule implicated in cell–cell and cell–matrix interactions and in cell signaling events (Chatterjee and Pandey, 2008). In addition, GALC downregulation may cause a decrease of the intracellular levels of ceramide and sphingosine, thus affecting cell survival and function (Visigalli et al., 2010). This possibility is supported also by the observation that psychosine levels do not correlate with nervous system regions exhibiting demyelination and axonopathy in twi-5J mice harboring a spontaneous missense Galc mutation (Potter et al., 2013) and that psychosine concentration within developing thymocytes does not correlate with the immune phenotype in twitcher mice (Galbiati et al., 2007). "
    [Show abstract] [Hide abstract] 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.
    Article · Apr 2016
    • "Also, our results reveal a new neuropathogenic aspect of globoid cell leukodystrophy in which the deficiency of GALC activity affects the ability of the blood microvasculature to respond to angiogenic stimuli not only in the nervous system but also in somatic organs. This may contribute to worsening globoid cell leukodystrophy disease evolution and may adversely affect therapeutic interventions, including bone marrow repopulation following haematopoietic stem cell transplantation (Visigalli et al., 2010). A better understanding of the role of the vascular system in globoid cell leukodystrophy may point the way towards new angioneurin-based molecular and cellular therapies (Zacchigna et al., 2008). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Sep 2013
    • "In this regard we have developed the hematopoietic stem cell (HSC)-based gene therapy for Krabbe disease, fatal LSD caused by mutations in the galactocerebrosidase (GALC) gene [125,126]. To be effective, this therapy needs the modulation of the transgene expression to avoid forced GALC toxicity [127]. The rationale of this approach was the inhibition of GALC toxicity in the HSCs used for GLD treatment in order to protect differentiated cells that could be able to carry efficiently their function. "
    [Show abstract] [Hide abstract] ABSTRACT: During the last few years microRNAs (miRNAs) have emerged as key mediators of post-transcriptional and epigenetic regulation of gene expression. MiRNAs targets, identified through gene expression profiling and studies in animal models, depict a scenario where miRNAs are fine-tuning metabolic pathways and genetic networks in both plants and animals. MiRNAs have shown to be differentially expressed in brain areas and alterations of miRNAs homeostasis have been recently correlated to pathological conditions of the nervous system, such as cancer and neurodegeneration. Here, we review and discuss the most recent insights into the involvement of miRNAs in the neurodegenerative mechanisms and their correlation with significant neurodegenerative disorders.
    Full-text · Article · Jun 2013
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