RESUMO
Neuronal amyloid-ß (Aß) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aß are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aß accumulation and associated neural deficits in a Drosophila model expressing Aß42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aß accumulation and associated synaptic and motor defects as well as premature death in Aß42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aß accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteínas de Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Metiltransferases/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Animais Geneticamente Modificados , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Drosophila , Feminino , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Atividade Motora/fisiologia , Neurônios/patologia , Fragmentos de Peptídeos/genética , Sinapses/metabolismoRESUMO
Sophoridine, a natural product obtained from medicinal plants, which has a variety of pharmacological effects, including anti-cancer effects, and selectively induces apoptotic cell death in a variety of human cancer cells in vitro and in vivo; however, its mechanism of action needs to be further elaborated. In this study, we investigated the effects of Sophoridine on the induction of apoptosis in human Glioma U87MG cells. Here, we found that Sophoridine can significantly inhibited cell proliferation, G2/M phase arrest, induced cell apoptosis and caused reactive oxygen species (ROS) generation and GSH content reduction. Sophoridine also triggered significant down-regulated the expression of p27, CDK2, Survivin, Livin, Bcl-2, E2F1 and the transcriptional activity of FoxM1, NF-κb and AP-1, meanwhile, up-regulated the expression of caspase-3/8, p53, Smac, c-JNK and p38-MAPK. Moreover, we found that Sophoridine significantly inhibited ubiquitin-proteasome in tumor cells. In conclusion, Sophoridine shows obvious anti-cancer activity on glioma cells by inducing cell apoptosis, inducing ROS accumulation, and activating mitochondrial signal pathways. Eventually, we believe Sophoridine could be used as a new drug for the treatment of glioma.