title: Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity.
abstract: A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
authors.forename: O G
authors.initials: OG
authors.lastname: Vidaurre
authors.forename: S
authors.initials: S
authors.lastname: Gascón
authors.forename: R
authors.initials: R
authors.lastname: Deogracias
authors.forename: M
authors.initials: M
authors.lastname: Sobrado
authors.forename: E
authors.initials: E
authors.lastname: Cuadrado
authors.forename: J
authors.initials: J
authors.lastname: Montaner
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Peña
authors.forename: M
authors.initials: M
authors.lastname: Díaz-Guerra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001344:Autopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D016086:Lentivirus; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010957:Plasmids; D061251:Primary Cell Culture; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D020813:Receptor, trkB