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Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene.
Nobile, Veronica; Palumbo, Federica; Lanni, Stella; Ghisio, Valentina; Vitali, Alberto; Castagnola, Massimo; Marzano, Valeria; Maulucci, Giuseppe; De Angelis, Claudio; De Spirito, Marco; Pacini, Laura; D'Andrea, Laura; Ragno, Rino; Stazi, Giulia; Valente, Sergio; Mai, Antonello; Chiurazzi, Pietro; Genuardi, Maurizio; Neri, Giovanni; Tabolacci, Elisabetta.
Afiliação
  • Nobile V; Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Roma, Italy.
  • Palumbo F; Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Roma, Italy.
  • Lanni S; Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada.
  • Ghisio V; UOC Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • Vitali A; Institute of Chemistry of Molecular Recognition, CNR, Roma, Italy.
  • Castagnola M; Istituto di Biochimica e Chimica Clinica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • Marzano V; Istituto di Biochimica e Chimica Clinica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • Maulucci G; Istituto di Biochimica e Chimica Clinica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • De Angelis C; Human Microbiome Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
  • De Spirito M; Istituto di Fisica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • Pacini L; Istituto di Fisica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • D'Andrea L; Istituto di Fisica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
  • Ragno R; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Stazi G; UniCamillus, Saint Camillus International University of Health and Medical Sciences, Rome, Italy.
  • Valente S; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Mai A; Department of Chemistry and Technologies of Drugs, Sapienza University, Rome, Italy.
  • Chiurazzi P; Department of Chemistry and Technologies of Drugs, Sapienza University, Rome, Italy.
  • Genuardi M; Department of Chemistry and Technologies of Drugs, Sapienza University, Rome, Italy.
  • Neri G; Department of Chemistry and Technologies of Drugs, Sapienza University, Rome, Italy.
  • Tabolacci E; Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Roma, Italy.
Hum Genet ; 139(2): 227-245, 2020 Feb.
Article em En | MEDLINE | ID: mdl-31919630
Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5' UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ataxia / Tremor / Metilação de DNA / Proteoma / Proteínas Mitocondriais / Proteína do X Frágil da Deficiência Intelectual / Síndrome do Cromossomo X Frágil / Mitocôndrias / Mutação Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ataxia / Tremor / Metilação de DNA / Proteoma / Proteínas Mitocondriais / Proteína do X Frágil da Deficiência Intelectual / Síndrome do Cromossomo X Frágil / Mitocôndrias / Mutação Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article