title: Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons.
abstract: During development as well as in pathological situations, neurons that fail to find appropriate targets or neurotrophic factors undergo cell death. Using primary cortical neurons subjected to acute serum-deprivation (SD), we have examined caspases activation, mitochondrial dysfunction and cell death parameters. Among a panel of metabolic, signaling and caspases inhibitors only those able to interfere with caspase-2 like activity protect primary neurons against SD-induced cell death. In situ detection and subcellular fractionation demonstrate a very early activation of cytosolic caspase-2, which controls Bax cleavage, relocalization and mitochondrial membrane permeabilization (MMP). Both z-VDVAD-fmk and a siRNA specific for caspase-2 abolish Bax changes, mitochondrial membranes permeabilization, as well as cytochrome c release-dependent activation of caspase-9/caspase-3, nuclear alterations, phosphatidylserine exposure, neurites dismantling and neuronal death. Hence, caspase-2 is an early checkpoint for apoptosis initiation in primary neurons subjected to serum deprivation.
authors.affiliation: Theraptosis Research Laboratory, Theraptosis S.A., Pasteur Biotop, Institut Pasteur, 25-28 Rue du Docteur Roux, 75015 Paris, France. dchauvier@theraptosis.com
authors.forename: D
authors.initials: D
authors.lastname: Chauvier
authors.forename: H
authors.initials: H
authors.lastname: Lecoeur
authors.forename: A
authors.initials: A
authors.lastname: Langonné
authors.forename: A
authors.initials: A
authors.lastname: Borgne-Sanchez
authors.forename: J
authors.initials: J
authors.lastname: Mariani
authors.forename: J-C
authors.initials: JC
authors.lastname: Martinou
authors.forename: D
authors.initials: D
authors.lastname: Rebouillat
authors.forename: E
authors.initials: E
authors.lastname: Jacotot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053143:Caspase 2 / Q000172:deficiency / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010455:Peptides / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D044967:Serum; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053143:Caspase 2