Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model

Sara Ricciardi, Elena M. Boggio, Stefano Grosso, Giuseppina Lonetti, Greta Forlani, Gilda Stefanelli, Eleonora Calcagno, Noemi Morello, Nicoletta Landsberger, Stefano Biffo, Tommaso Pizzorusso, Maurizio Giustetto, Vania Broccoli

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Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder with no efficient treatment that is caused in the majority of cases by mutations in the gene methyl-CpG binding-protein 2 (MECP2). RTT becomes manifest after a period of apparently normal development and causes growth deceleration, severe psychomotor impairment and mental retardation. Effective animal models for RTT are available and show morphofunctional abnormalities of synaptic connectivity. However, the molecular consequences of MeCP2 disruption leading to neuronal and synaptic alterations are not known. Protein synthesis regulation via the mammalian target of the rapamycin (mTOR) pathway is crucial for synaptic organization, and its disruption is involved in a number of neurodevelopmental diseases. We investigated the phosphorylation of the ribosomal protein (rp) S6, whose activation is highly dependent from mTOR activity. Immunohistochemistry showed that rpS6 phosphorylation is severely affected in neurons across the cortical areas of Mecp2 mutants and that this alteration precedes the severe symptomatic phase of the disease. Moreover, we found a severe defect of the initiation of protein synthesis in the brain of presymptomatic Mecp2 mutant that was not restricted to a specific subset of transcripts. Finally, we provide evidence for a general dysfunction of the Akt/mTOR, but not extracellular-regulated kinase, signaling associated with the disease progression in mutant brains. Our results indicate that defects in the AKT/mTOR pathway are responsible for the altered translational control in Mecp2 mutant neurons and disclosed a novel putative biomarker of the pathological process. Importantly, this study provides a novel context of therapeutic interventions that can be designed to successfully restrain or ameliorate the development of RTT.

Original languageEnglish
Article numberddq563
Pages (from-to)1182-1196
Number of pages15
JournalHuman Molecular Genetics
Volume20
Issue number6
DOIs
Publication statusPublished - Mar 2011

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Ricciardi, S., Boggio, E. M., Grosso, S., Lonetti, G., Forlani, G., Stefanelli, G., Calcagno, E., Morello, N., Landsberger, N., Biffo, S., Pizzorusso, T., Giustetto, M., & Broccoli, V. (2011). Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Human Molecular Genetics, 20(6), 1182-1196. [ddq563]. https://doi.org/10.1093/hmg/ddq563