Abstract：
Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.
摘要：
嘧啶束结合蛋白1（PTBP1）在肿瘤进展和神经发生过程中调节多种可变剪接事件。以前,据报道，PTBP1下调可将星形胶质细胞转化为功能性神经元；然而，PTBP1如何调节星形胶质细胞生理学尚不清楚.在这项研究中,我们发现PTBP1通过ATP1a2调节谷氨酸的摄取，ATP1a2是Na+/K+-ATP酶的成员，和星形胶质细胞中的谷氨酸转运蛋白。Ptbp1敲低改变线粒体功能和能量代谢，其中PTBP1通过琥珀酸脱氢酶（SDH）/Nrf2途径调节线粒体氧化还原稳态。Ptbp1敲低后谷氨酸转运蛋白的功能障碍导致皮质中兴奋性突触传递增强。值得注意的是,我们开发了仿生阳离子三嵌段多肽系统，即，聚乙二醇44-polylysine30-polyleucine10（PEG44-PLL30-PLLeu10）与星形细胞膜涂层在体外和体内递送Ptbp1siRNA，这种方法允许Ptbp1siRNA有效地穿过血脑屏障并靶向大脑中的星形胶质细胞。总的来说，我们的研究结果提出了一个框架，PTBP1作为谷氨酸运输机制的调节剂，并表明仿生方法是体内siRNA递送的有希望的途径。
