Protein cereblon

Protein cereblon (CRBN) is a substrate recognition component of a DCX E3 ubiquitin ligase complex that targets proteins like MEIS2, ILF2, and GLUL for proteasomal degradation (UniProt: Q96SW2). Beyond canonical ubiquitination, CRBN maintains presynaptic glutamate release and cognitive functions by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons, likely through assembly and surface expression of BK channel complexes via interaction with KCNT1. CRBN also suppresses TLR4 signaling by inhibiting ECSIT ubiquitination.

CRBN is implicated in intellectual developmental disorder, autosomal recessive 2 (MRT2; MIM 607417), characterized by mild intellectual disability and developmental delay (UniProt: Q96SW2). Its roles in limb development, glutamatergic signaling, and anxiety-related behaviors underscore its importance in neurodevelopment.

In Alzheimer's disease, CRBN is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2 fold-change: −0.94; Chaparral AD proteomics). This reduction may compromise cognitive functions dependent on glutamatergic neurotransmission and BK channel regulation, potentially contributing to AD-associated memory and learning impairment.