Affiliation: | (1) Theraptosis Research Laboratory, Theraptosis S.A., Pasteur Biotop, Institut Pasteur, 25-28 Rue du Docteur Roux, 75015 Paris, France;(2) UMR CNRS 7102 and Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France;(3) Department of Cell Biology, Sciences III, University of Geneva, Geneva 4, Switzerland;(4) Present address: Theraptosis, Institut Pasteur, Pasteur BioTop, 28 rue du Dr. Roux, F-75724 Paris cedex 15, France |
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. D. Rebouillat and E. Jacotot share senior co-authorship. |