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Title: Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice
Author: Jorge Torres, Olga C.
Szczesna, Karolina
Roa, Laura
Casal, Carmen
Gonzalez Somermeyer, Louisa
Soler, Marta
Velasco, Cecilia D.
Martinez San Segundo, Pablo
Petazzi, Paolo
Sáez, Mauricio A.
Delgado Morales, Raul
Fourcade, Stéphane
Pujol Onofre, Aurora
Huertas, Dori
Llobet Berenguer, Artur, 1972-
Guil, Sonia
Esteller, Manel
Keywords: Síndrome de Rett
Enginyeria de proteïnes
Rett syndrome
Protein engineering
Issue Date: 8-May-2018
Publisher: Elsevier
Abstract: Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG- binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.
Note: Reproducció del document publicat a:
It is part of: Cell Reports, 2018, vol. 23, num. 6, p. 1665-1677
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ISSN: 2211-1247
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Neurociències (UBNeuro))

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