The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Accumulated evidence shows that FBXW7 is fundamental to neurological functions and especially implicated in neurodevelopment and the nosogenesis of neurodegeneration. In this review, we describe general features of FBXW7 gene and proteins, and mainly present recent findings that highlight the vital roles and molecular mechanisms of FBXW7 in neurodevelopment such as neurogenesis, myelination and cerebral vasculogenesis and in the pathogenesis of some typical neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Additionally, we also provide a prospect on focusing FBXW7 as a potential therapeutic target to rescue neurodevelopmental and neurodegenerative impairment.

Abstractc-Jun activation domain binding protein-1 (JAB1) is a multifunctional regulator that plays vital roles in diverse cellular processes. It regulates AP-1 transcriptional activity and also acts as the fifth component of the COP9 signalosome complex. While JAB1 is considered an oncoprotein that triggers tumor development, recent studies have shown that it also functions in neurological development and disorders. In this review, we summarize the general features of the JAB1 gene and protein, and present recent updates on the regulation of JAB1 expression. Moreover, we also highlight the functional roles and regulatory mechanisms of JAB1 in neurodevelopmental processes such as neuronal differentiation, synaptic morphogenesis, myelination, and hair cell development and in the pathogenesis of some neurological disorders such as Alzheimer’s disease, multiple sclerosis, neuropathic pain, and peripheral nerve injury. Furthermore, current challenges and prospects are discussed, including updates on drug development targeting JAB1.

Regulator of calcineurin 1 (RCAN1), a crucial endogenous regulator of calcineurin, is implicated in multiple important physiological and pathological processes. Aberrant expression of RCAN1 is commonly found in brains of patients with Down syndrome (DS) or Alzheimer’s disease (AD), accounting for impaired neurodevelopment in DS and neuronal degeneration in AD, respectively. However, the mechanism of RCAN1 in brain development and neurodegeneration remains unclear. FBXW7 functions as vital factor in neurodevelopment and neurodegeneration via mediating proteasomal degradation of its substrates. Deficiency of FBXW7 contributes to impaired neurodevelopment and accelerating neurodegeneration. Here, we show that increased RCAN1 reduces the level of β isoform of FBXW7 (FBXW7β). RCAN1 inhibits FBXW7β transcription in a calcineurin dependent manner. Potential NFAT binding sites are identified within the promoter of FBXW7β, and NFAT is also demonstrated to activate the promoter activity of FBXW7β. In summary, our work implies that RCAN1 can regulate FBXW7β expression by inhibiting FBXW7β transcription via calcineurin/NFAT signaling pathway. It could provide more understanding on the mechanism of FBXW7 regulation and suggest a potential mechanism on functional implication of RCAN1 with impaired brain function in some neurodevelopmental and neurodegenerative diseases.