부산대학교 도서관

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), 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 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 ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.
Synopsis: Intellectual disability is a major healthcare issue. Mutations in the human cereblon/CRBN gene cause a form of non-syndromic intellectual disability that is recapitulated in Crbn knockout mice. However, the neuropathological bases of this orphan disease are currently unknown.The pool of CRBN molecules selectively located on telencephalic glutamatergic neurons is necessary for proper memory function in mice.CRBN interacts physically with the intracellular domain of the cannabinoid CB1 receptor, and thereby inhibits receptor action in a ubiquitin ligase-independent manner.The cannabinoid CB1 receptor is overactivated in the hippocampus of Crbn-deficient mice.The memory shortfalls shown by Crbn-deficient mice are rescued by the acute administration of a cannabinoid CB1 receptor-selective antagonist.
Intellectual disability is a major healthcare issue. Mutations in the human cereblon/CRBN gene cause a form of non-syndromic intellectual disability that is recapitulated in Crbn knockout mice. However, the neuropathological bases of this orphan disease are currently unknown.