RT Journal Article
T1 The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls
A1 Costas Insúa, Carlos
A1 Hermoso López, Alba
A1 Moreno, Estefanía
A1 Montero Fernández, Carlos
A1 Álvaro Blázquez, Alicia
A1 Maroto, Irene
A1 Sánchez Ruíz, Andrea
A1 Díez Alarcia, Rebeca
A1 Blázquez Ortiz, Cristina
A1 Morales, Paula
A1 Canela, Enric
A1 Casadó, Vicent
A1 Urigüen, Leyre
A1 Perea, Gertrudis
A1 Bellocchio, Luigi
A1 Rodríguez Crespo, José Ignacio
A1 Guzmán Pastor, Manuel
AB Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), akey suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligaseindependent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiencylinked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.
PB EMBO Press
SN 1757-4684
YR 2024
FD 2024
LK https://hdl.handle.net/20.500.14352/114201
UL https://hdl.handle.net/20.500.14352/114201
LA eng
NO Carlos Costas-Insua; Alba Hermoso-López; Estefanía Moreno; Carlos Montero-Fernández; Alicia Álvaro-Blázquez; Irene B Maroto; Andrea Sánchez-Ruiz; Rebeca Diez-Alarcia; Cristina Blázquez; Paula Morales et al.
DS Docta Complutense
RD 22 abr 2025