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Iron Loading Selectively Increases Hippocampal Levels of Ubiquitinated Proteins and Impairs Hippocampus-Dependent Memory

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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.

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Acknowledgments

This research was supported by the National Council for Scientific and Technological Development (CNPq). L.S.F. is supported by a CAPES/MEC fellowship. V.A.D. is supported by a CNPq/PIBIC scholarship and L.M.K. is supported by a BPA/PUCRS scholarship. L.W.K. is recipient of fellowship CAPES/PNPD Program. M.R.B. and N.S. are Research Career Awardees of the CNPq.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, Porto Alegre, RS, Brazil

    Luciana Silva Figueiredo, Betânia Souza de Freitas, Vanessa Athaíde Garcia, Vinícius Ayub Dargél & Luiza Machado Köbe

  2. 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

    Luiza Wilges Kist & Maurício Reis Bogo

  3. 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

    Luiza Wilges Kist & Maurício Reis Bogo

  4. Faculty of Biosciences, Pontifical Catholic University, Av. Ipiranga, 6681 Prédio 12D, Sala 301, 90619-900, Porto Alegre, RS, Brazil

    Nadja Schröder

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  1. Luciana Silva Figueiredo
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  2. Betânia Souza de Freitas
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Figueiredo, L.S., de Freitas, B.S., Garcia, V.A. et al. Iron Loading Selectively Increases Hippocampal Levels of Ubiquitinated Proteins and Impairs Hippocampus-Dependent Memory. Mol Neurobiol 53, 6228–6239 (2016). https://doi.org/10.1007/s12035-015-9514-6

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