PMID- 21212100
OWN - NLM
STAT- MEDLINE
DCOM- 20110620
LR  - 20231120
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 20
IP  - 6
DP  - 2011 Mar 15
TI  - Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome 
      animal model.
PG  - 1182-96
LID - 10.1093/hmg/ddq563 [doi]
AB  - 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.
FAU - Ricciardi, Sara
AU  - Ricciardi S
AD  - Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele 
      Scientific Institute, 20132 Milano, Italy.
FAU - Boggio, Elena M
AU  - Boggio EM
FAU - Grosso, Stefano
AU  - Grosso S
FAU - Lonetti, Giuseppina
AU  - Lonetti G
FAU - Forlani, Greta
AU  - Forlani G
FAU - Stefanelli, Gilda
AU  - Stefanelli G
FAU - Calcagno, Eleonora
AU  - Calcagno E
FAU - Morello, Noemi
AU  - Morello N
FAU - Landsberger, Nicoletta
AU  - Landsberger N
FAU - Biffo, Stefano
AU  - Biffo S
FAU - Pizzorusso, Tommaso
AU  - Pizzorusso T
FAU - Giustetto, Maurizio
AU  - Giustetto M
FAU - Broccoli, Vania
AU  - Broccoli V
LA  - eng
GR  - GGP07181/TI_/Telethon/Italy
GR  - GGP09196/TI_/Telethon/Italy
GR  - GGP10032/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110106
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Mecp2 protein, mouse)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - *Down-Regulation
MH  - Humans
MH  - Methyl-CpG-Binding Protein 2/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neurons/metabolism
MH  - Oncogene Protein v-akt/genetics/*metabolism
MH  - *Protein Biosynthesis
MH  - Rett Syndrome/genetics/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
EDAT- 2011/01/08 06:00
MHDA- 2011/06/21 06:00
CRDT- 2011/01/08 06:00
PHST- 2011/01/08 06:00 [entrez]
PHST- 2011/01/08 06:00 [pubmed]
PHST- 2011/06/21 06:00 [medline]
AID - ddq563 [pii]
AID - 10.1093/hmg/ddq563 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2011 Mar 15;20(6):1182-96. doi: 10.1093/hmg/ddq563. Epub 2011 Jan 
      6.