title: Deregulation of calcium homeostasis mediates secreted α-synuclein-induced neurotoxicity.
abstract: α-Synuclein (AS) plays a crucial role in Parkinson's disease pathogenesis. AS is normally secreted from neuronal cells and can thus exert paracrine effects. We have previously demonstrated that naturally secreted AS species, derived from SH-SY5Y cells inducibly overexpressing human wild type AS, can be toxic to recipient neuronal cells. In the current study, we show that application of secreted AS alters membrane fluidity and increases calcium (Ca2+) entry. This influx is reduced on pharmacological inhibition of voltage-operated Ca2+ channels. Although no change in free cytosolic Ca2+ levels is observed, a significantly increased mitochondrial Ca2+ sequestration is found in recipient cells. Application of voltage-operated Ca2+ channel blockers or Ca2+ chelators abolishes AS-mediated toxicity. AS-treated cells exhibit increased calpain activation, and calpain inhibition greatly alleviates the observed toxicity. Collectively, our data suggest that secreted AS exerts toxicity through engagement, at least in part, of the Ca2+ homeostatic machinery. Therefore, manipulating Ca2+ signaling pathways might represent a potential therapeutic strategy for Parkinson's disease.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Melachroinou
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Evangelia
authors.initials: E
authors.lastname: Emmanouilidou
authors.forename: Roser
authors.initials: R
authors.lastname: Masgrau
authors.forename: Panagiota
authors.initials: P
authors.lastname: Papazafiri
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
authors.forename: Kostas
authors.initials: K
authors.lastname: Vekrellis
mesh_terms: D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism / Q000633:toxicity*
chemical_list: D002121:Calcium Channel Blockers; D002614:Chelating Agents; D051844:alpha-Synuclein; D002118:Calcium
keywords: Alpha-synuclein; Calpains; Exosomes; Membrane fluidity; Mitochondria; Neurodegeneration; Parkinson's disease; Secretion