Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model
Open accessAbstract
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.
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In animal models of autism spectrum disorder, altered mTORC1 signaling contributes to synaptic dysfunction and aberrant network connectivity.
“Additionally in animal models of autism spectrum disorder (ASD), altered mTORC1 signaling contributes to the observed synaptic dysfunction and aberrant network connectivity (13,15,(21)(22)(23)(24)(25)(26)(27).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [15]
The Discussion (page unavailable) reports reduced AKT/mTOR signaling in Mecp2-mutant Rett syndrome brains and associates it with reduced synaptic connectivity and impaired network performance. It says the molecular defects might contribute to synapse loss, rather than establishing causation, and does not specifically identify mTORC1 or demonstrate the claim across ASD animal models. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBecause MET converts extracellular cues into mTOR activation, the ASD-linked MET C variant is expected to reduce mTOR signaling.
“MET translates extracellular signals into mTOR activation; thus, the ASD-related MET C variant is predicted to lead to hypoactive mTOR signalling231.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [231]
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Self-citation
- Authors
- 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.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Neuroscience Institute (IT)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Florence (IT)
- University of Insubria (IT)
- University of Turin (IT)
- Corresponding author
- Giustetto, Maurizio
- Broccoli, Vania
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-01-06
- Volume
- 20
- Issue
- 6
- Pages
- 1182-1196
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2157536563
- Cited by
- 223
- References
- 7
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 14 · 2022: 10 · 2021: 11 · 2020: 16 · 2019: 6 · 2018: 15 · 2017: 21 · 2016: 27 · 2015: 29 · 2014: 20 · 2013: 18 · 2012: 10
- FWCI
- 10.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Human Molecular Genetics (publishedVersion, public-domain)
- PubMed (publishedVersion)
- IrInSubria (University of Insubria) (submittedVersion, public-domain)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Compagnia di San Paolo
- E-Rare
- Regione Piemonte
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- Rett syndrome, MeCP2, Akt/mTOR signaling, S6 phosphorylation, translational regulation, protein synthesis initiation, neurodevelopmental disorders, synaptic dysfunction, biomarkers, therapeutic target
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mice, Inbred C57BL, Neurons, Protein Biosynthesis, Signal Transduction, Rett Syndrome, Down-Regulation, Mice, Knockout, Oncogene Protein v-akt, Mice, Methyl-CpG-Binding Protein 2, TOR Serine-Threonine Kinases
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