Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transpo Show more
Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset. Dietary CBD was administered daily (80-100 mg/kg/day) in male There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance. Show less
RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors t Show more
RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors. Show less