title: FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: basal contents and effects of psychotropic treatments.
abstract: Enhanced brain apoptosis (neurons and glia) may be involved in major depression (MD) and schizophrenia (SZ), mainly through the activation of the intrinsic (mitochondrial) apoptotic pathway. In the extrinsic death pathway, pro-apoptotic Fas-associated death domain (FADD) adaptor and its non-apoptotic p-Ser194 FADD form have critical roles interacting with other death regulators such as phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) and extracellular signal-regulated kinase (ERK). The basal status of FADD (protein and messenger RNA (mRNA)) and the effects of psychotropic drugs (detected in blood/urine samples) were first assessed in postmortem prefrontal cortex of MD and SZ subjects (including a non-MD/SZ suicide group). In MD, p-FADD, but not total FADD (and mRNA), was increased (26%, n=24; all MD subjects) as well as p-FADD/FADD ratio (a pro-survival marker) in antidepressant-free MD subjects (50%, n=10). In contrast, cortical FADD (and mRNA), p-FADD, and p-FADD/FADD were not altered in SZ brains (n=21) regardless of antipsychotic medications (except enhanced mRNA in treated subjects). Similar negative results were quantified in the non-MD/SZ suicide group. In MD, the regulation of multifunctional PEA-15 (i.e., p-Ser116 PEA-15 blocks pro-apoptotic FADD and PEA-15 prevents pro-survival ERK action) and the modulation of p-ERK1/2 were also investigated. Cortical p-PEA-15 was not changed whereas PEA-15 was increased mainly in antidepressant-treated subjects (16-20%). Interestingly, cortical p-ERK1/2/ERK1/2 ratio was reduced (33%) in antidepressant-free when compared to antidepressant-treated MD subjects. The neurochemical adaptations of brain FADD (increased p-FADD and pro-survival p-FADD/FADD ratio), as well as its interaction with PEA-15, could play a major role to counteract the known activation of the mitochondrial apoptotic pathway in MD.
authors: Laboratorio de Neurofarmacología, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), and Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors: M J
authors: MJ
authors: García-Fuster
authors: Departamento de Farmacología and Instituto Biocruces, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), E-48940 Leioa, Bizkaia, Spain.
authors: R
authors: R
authors: Díez-Alarcia
authors: Laboratorio de Neurofarmacología, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), and Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors: M
authors: M
authors: Ferrer-Alcón
authors: Centre Universitaire Romand de Médecine Légale - Site Genève, University of Geneva, CH-1211 Geneva 4, Switzerland.
authors: R
authors: R
authors: La Harpe
authors: Departamento de Farmacología and Instituto Biocruces, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), E-48940 Leioa, Bizkaia, Spain.
authors: J J
authors: JJ
authors: Meana
authors: Laboratorio de Neurofarmacología, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), and Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain. Electronic address: jesus.garcia-sevilla@uib.es.
authors: J A
authors: JA
authors: García-Sevilla
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D013405:Suicide
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D051017:Apoptosis Regulatory Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: FADD adaptor; MAP kinases; PEA-15; major depression; psychotropic drugs; schizophrenia