title: Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model.
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.
authors.affiliation: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.forename: Elena M
authors.initials: EM
authors.lastname: Boggio
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Lonetti
authors.forename: Greta
authors.initials: G
authors.lastname: Forlani
authors.forename: Gilda
authors.initials: G
authors.lastname: Stefanelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Calcagno
authors.forename: Noemi
authors.initials: N
authors.lastname: Morello
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giustetto
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases