Investigating the Molecular Pathogenic Mechanism Underlying Mutant Cul4b-Induced X-Linked Mental Retardation.( I )

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Mental retardation/intellectual disability is found in ~1-2% of the human population and more prevalent in males than in females. The etiology of mental retardation is very heterogeneous, and the most prevalent cause, which accounts for 10-15% of all types of mental retardation (MR), is the X-linked mental retardation (XLMR) caused by mutations at various loci of X chromosome. Molecular genetic studies demonstrated that truncating or missense mutations of cullin 4B (CUL4B) gene located on the Xq24-q25 locus were observed in male MR patients. CUL4B mutation is one of the most frequently mutated genes underlying XLMR. Better understanding of pathogenic mechanism underlying mutant CUL4B-induced cognitive impairment is essential for developing therapeutic strategy for mental retardation caused by mutations of CUL4B or other X-chromosome genes. Up to now, molecular pathogenic mechanism of mutant CUL4B-induced MR has not been investigated in detail. CUL4B binds to ROC1 or ROC2, resulting in the formation of CUL4B–RING E3 ubiquitin ligase. Previous studies using cell lines showed that CUL4B-RING E3 ubiquitin ligase mediates ubiquitylation and degradation of proteins, which are implicated in DNA replication, cell cycle control, signal transduction and development. Abnormal neuronal development and function in the frontal lobe, amygdala and hippocampus is involved in the pathogenesis of XLMR. CUL4B mRNA is highly expressed in the neurons of the cerebral cortex, amygdala and hippocampus. Up to now, neuronal substrates of CUL4B–RING E3 ubiquitin ligase-mediated ubiquitylation and physiological functions of CUL4B in the brain still remain unknown. Our recent results using cultured neocortical neurons of frontal lobe indicated that CUL4B-RING E3 ligase positively regulates mTOR activity by promoting the degradation of TSC2, which is a major negative regulator of mTOR signaling. On the other hand, XLMR (R388X), (R572C) or (V745A) CUL4B mutation impairs CUL4B-RING E3 ligase-mediated ubiquitylation and degradation of TSC2. The mTOR signaling, which promotes local protein synthesis in the dendrites and spines, is required for dendritic arborization, spine formation/morphogenesis and synaptic plasticity including late-long-term potentiation (LTP) and mGluR-dependent long-term depression (mGluR-LTD). CUL4B, which acts a positive regulator of mTOR signaling pathway, could play a crucial role in cognitive function by regulating dendritic development, spine formation/maturation, late-LTP and mGluR-LTD in the cerebral cortex, amygdala and hippocampus. XLMR mutation-induced loss of CUL4B function in male MR patients is likely to cause accumulation of TSC2 and resulting inhibition of mTOR activity in the brain, leading to an impairment of neuronal development, synaptic plasticity and cognitive function. Further study using knockin mouse model, which expresses XLMR mutant CUL4B, is required to investigate cellular and molecular mechanisms of mutant CUL4B-induced cognitive impairment. In the present study, male knockin mouse expressing mutant (R629C) or (V802A) CUL4B, which corresponds to mutant (R572C) or (V745A) CUL4B found in male MR patients, is prepared as an animal model of mutant CUL4B-induced mental retardation/intellectual disability. Then, male CUL4BR629C or CUL4BV802A knockin mice, which display behavioral deficits of cognitive dysfunction, are used to study molecular pathogenic mechanism underlying mutant CUL4B-induced mental retardation and physiological functions of CUL4B in the brain by performing the following

Project IDs

Project ID:PC10109-0139
External Project ID:NSC101-2321-B182-011
StatusFinished
Effective start/end date01/08/1231/07/13

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