title: Role of extracellular calcium and mitochondrial oxygen species in psychosine-induced oligodendrocyte cell death.
abstract: Globoid cell leukodystrophy (GLD) is a metabolic disease caused by mutations in the galactocerebrosidase (GALC) gene. GALC is a lysosomal enzyme whose function is to degrade galacto-lipids, including galactosyl-ceramide and galactosyl-sphingosine (psychosine, PSY). GALC loss of function causes progressive intracellular accumulation of PSY. It is widely held that PSY is the main trigger for the degeneration of myelinating cells and progressive white-matter loss. However, still little is known about the molecular mechanisms by which PSY imparts toxicity. Here, we address the role of calcium dynamics during PSY-induced cell death. Using the human oligodendrocyte cell line MO3.13, we report that cell death by PSY is accompanied by robust cytosolic and mitochondrial calcium (Ca(2+)) elevations, and by mitochondrial reactive oxygen species (ROS) production. Importantly, we demonstrate that the reduction of extracellular calcium content by the chelating agent ethylenediaminetetraacetic acid can decrease intra-mitochondrial ROS production and enhance cell viability. Antioxidant administration also reduces mitochondrial ROS production and cell loss, but this treatment does not synergize with Ca(2+) chelation. Our results disclose novel intracellular pathways involved in PSY-induced death that may be exploited for therapeutic purposes to delay GLD onset and/or slow down its progression.
authors.affiliation: NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Voccoli
authors.affiliation: NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Tonazzini
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Signore
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Caleo
authors.affiliation: NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cecchini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D065096:Calcium Chelating Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011609:Psychosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D065096:Calcium Chelating Agents; D003470:Culture Media; D017382:Reactive Oxygen Species; D011609:Psychosine; D004492:Edetic Acid; D002118:Calcium; D000111:Acetylcysteine