title: Cofilin activation mediates Bax translocation to mitochondria during excitotoxic neuronal death.
abstract: During excitotoxic neuronal death, Bax translocates to the mitochondria where it plays an important role by contributing to the release of proapoptotic factors. However, how Bax translocates to the mitochondria during excitotoxicity remains poorly understood. Herein, our data suggest the presence of a novel signalling mechanism by which NMDA receptor stimulation promotes Bax translocation. This signalling pathway is triggered by dephosphorylation of cofilin. Once dephosphorylated, cofilin might interact physically with Bax acting as a carrier for it, translocating it to the mitochondria, where it contributes to mitochondrial membrane despolarization, permeabilization and to the release of apoptotic factors, thus leading to neuronal death. Lack-of-function studies indicate that only the Slingshot family of phosphatases, more specifically the enzyme Slingshot 1L phosphatase, but not cronophin participates in the cofilin activation process during excitotoxicity. Indeed, cofilin-mediated Bax translocation seems to be a key event in excitotoxic neuronal death as knock down of either cofilin or Slingshot 1L phosphatase has a marked neuroprotective effect on NMDA-mediated neuronal death. This novel biochemical pathway may therefore be a good target to develop future therapeutic molecules for neurodegenerative diseases.
authors: Departamento de Ciencias Médicas, Unidad Asociada Neurodeath, CSIC-Universidad de Castilla-La Mancha, Albacete, Spain.
authors: Inmaculada
authors: I
authors: Posadas
authors: Francisco C
authors: FC
authors: Pérez-Martínez
authors: Javier
authors: J
authors: Guerra
authors: Prado
authors: P
authors: Sánchez-Verdú
authors: Valentín
authors: V
authors: Ceña
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494828:Bax protein, rat; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D018690:Excitatory Amino Acid Agonists; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein