Background: Deficiency or nonsense mutation of CRBN causes memory deficits. Results: Truncated CRBN has insufficient affinity for AMPK␣ and cannot modulate the AMPK-mTOR pathway. Conclusion: CRBN modulates protein synthesis through the AMPK-mTOR pathway, and may be critical for certain forms of memory encoding. Significance: Our findings suggest the first plausible mechanism for the phenotype resulting from the CRBN mutation.
Initially identified as a protein implicated in human mental deficit, cereblon (CRBN) was recently recognized as a negative regulator of adenosine monophosphate‐activated protein kinase (AMPK) in vivo and in vitro. Here, we present results showing that CRBN can effectively regulate new protein synthesis through the mammalian target of rapamycin (mTOR) signaling pathway, a downstream target of AMPK. Whereas deficiency of Crbn repressed protein translation via activation of the AMPK‐mTOR cascade in Crbn‐knockout mice, ectopic expression of the wild‐type CRBN increased protein synthesis by repressing endogenous AMPK. Unlike the wild‐type CRBN, a mutant CRBN found in human patients, which lacks the last 24 amino acids, failed to rescue mTOR‐dependent repression of protein synthesis in Crbn‐deficient mouse fibroblasts. These results provide the first evidence that Crbn can activate the protein synthesis machinery through the mTOR signaling pathway by inhibiting AMPK. In light of the fact that protein synthesis regulated by mTOR is essential for various forms of synaptic plasticity that underlie the cognitive functions of the brain, the results of this study suggest a plausible mechanism for CRBN involvement in higher brain function in humans, and they may help explain how a specific mutation in CRBN can affect the cognitive ability of patients.
Grant Funding Source: Supported by Ministry for Health and Welfare [HI13C1412] and Ministry of Science, ICT & Future Planning of Korea [2007‐0056157] [2011‐0028665] of Korea.
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