The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche
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.
Full-textDOI: · Available from: Sabata Martino, Sep 03, 2015
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- "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 . 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. "
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.Genes 06/2013; 4(2):244-63. DOI:10.3390/genes4020244 · 1.15 Impact Factor
Trends in Stem Cell Proliferation and Cancer Research, Edited by Resende, Rodrigo; Ulrich, Henning, chapter The role of sphingolipids in modulating pluripotency of stem cells; Springer., ISBN: 978-94-007-6210-7
- "Galactosylceramidase catalyzes hydrolytic removal of galactose from galactosylceramide or galactosylsphingosine , yielding ceramide or sphingosine, respectively. It was reported that galactosylceramidase was involved in maintaining a functional hematopoietic stem cell niche by control of the intracellular ceramide and sphingosine levels (Visigalli et al. 2010). Direct evidence of GSLs modulating stem cell character comes from the study of a GCS-knockout mouse (Yamashita et al. 1999). "
Article: Gene therapy for leukodystrophies[Show abstract] [Hide abstract]
ABSTRACT: Leukodystrophies (LDs) refer to a group on inherited diseases in which molecular abnormalities of glial cells are responsible for exclusive or predominant defects in myelin formation and/or maintenance within the central and, sometimes, the peripheral nervous system. For three of them [X-linked adrenoleukodystrophy (X-ALD), metachromatic (MLD) and globoid cell LDs], a gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD. Long-term follow-up has shown that HSCs gene therapy can arrest the devastating progression of X-ALD. Brain gene therapy relying upon intracerebral injections of adeno-associated vectors is also envisaged for MLD. The development of new gene therapy viral vectors allowing targeting of the disease gene into oligodendrocytes or astrocytes should soon benefit other forms of LDs.Human Molecular Genetics 03/2011; 20(R1):R42-53. DOI:10.1093/hmg/ddr142 · 6.39 Impact Factor