title: Iron Loading Selectively Increases Hippocampal Levels of Ubiquitinated Proteins and Impairs Hippocampus-Dependent Memory.
abstract: Alterations of brain iron levels have been observed in a number of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in the adulthood. Protein degradation mediated by the ubiquitin-proteasome system (UPS) plays a central regulatory role in several cellular processes. Impairment of the UPS has been implicated in the pathogenesis of neurodegenerative disorders. Here, we examined the effects of iron exposure in the neonatal period (12th-14th day of postnatal life) on the expression of proteasome β-1, β-2, and β-5 subunits, and ubiquitinated proteins in brains of 15-day-old rats, to evaluate the immediate effect of the treatment, and in adulthood to assess long-lasting effects. Two different memory types, emotionally motivated conditioning and object recognition were assessed in adult animals. We found that iron administered in the neonatal period impairs both emotionally motivated and recognition memory. Polyubiquitinated protein levels were increased in the hippocampus, but not in the cortex, of adult animals treated with iron. Gene expression of subunits β1 and β5 was affected by age, being higher in the early stages of development in the hippocampus, accompanied by an age-related increase in polyubiquitinated protein levels in adults. In the cortex, gene expression of the three proteasome subunits was significantly higher in adulthood than in the neonatal period. These findings suggest that expression of proteasome subunits and activity are age-dependently regulated. Iron exposure in the neonatal period produces long-lasting harmful effects on the UPS functioning, which may be related with iron-induced memory impairment.
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil.
authors.forename: Luciana Silva
authors.initials: LS
authors.lastname: Figueiredo
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil.
authors.forename: Betânia Souza
authors.initials: BS
authors.lastname: de Freitas
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil.
authors.forename: Vanessa Athaíde
authors.initials: VA
authors.lastname: Garcia
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil.
authors.forename: Vinícius Ayub
authors.initials: VA
authors.lastname: Dargél
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil.
authors.forename: Luiza Machado
authors.initials: LM
authors.lastname: Köbe
authors.affiliation: Laboratório de Biologia Genômica e Molecular, Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Avenida Ipiranga, 6681, 90619-900, Porto Alegre, RS, Brazil.|Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Avenida Ipiranga, 6690, 90610-000, Porto Alegre, RS, Brazil.
authors.forename: Luiza Wilges
authors.initials: LW
authors.lastname: Kist
authors.affiliation: Laboratório de Biologia Genômica e Molecular, Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Avenida Ipiranga, 6681, 90619-900, Porto Alegre, RS, Brazil.|Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Avenida Ipiranga, 6690, 90610-000, Porto Alegre, RS, Brazil.
authors.forename: Maurício Reis
authors.initials: MR
authors.lastname: Bogo
authors.affiliation: Faculty of Biosciences, Pontifical Catholic University, Av. Ipiranga, 6681 Prédio 12D, Sala 301, 90619-900, Porto Alegre, RS, Brazil. nadja.schroder@pucrs.br.
authors.forename: Nadja
authors.initials: N
authors.lastname: Schröder
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D057149:Ubiquitinated Proteins; D025821:Polyubiquitin; D007501:Iron; D046988:Proteasome Endopeptidase Complex
keywords: Iron; Memory; Neurodegenerative disorders; Ubiquitin-proteasome system; β-proteasome subunits