Abstract summary 

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 CB receptor (CBR), a key 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 CBR-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CBR and impairs the CBR-G-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CBR overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CBR could constitute a new therapy for this orphan disease.

Authors & Co-authors:  Costas-Insua Hermoso-López Moreno Montero-Fernández Álvaro-Blázquez Maroto Sánchez-Ruiz Diez-Alarcia Blázquez Morales Canela Casadó Urigüen Perea Bellocchio Rodríguez-Crespo Guzmán

Study Outcome 

Source Link: Visit source