Stabilization of primary cilia reduces abortive cell cyle re-entry to protect injured adult CNS neurons from apoptosis

Abortive cell cycle (ACC) re-entry of apoptotic neurons is a recently characterized phenomenon that occurs after central nervous system (CNS) injury or over the course of CNS disease. Consequently, inhibiting cell cycle progression is neuroprotective in numerous CNS pathology models. Primary cilia are ubiquitous, centriole-based cellular organelles that prevent cell cycling, but their ability to modulate abortive cell cycle has not been described. Here, we show that neuronal cilia are ablated in-vitro and in-vivo following injury by hypoxia or optic nerve transection (ONT), respectively. Furthermore, forced cilia resorption sensitized neurons to these injuries and enhanced cell death. In contrast, pharmacological inhibition or shRNA knockdown of the proteins that disassemble the cilia increased neuron survival and decreased the phosphorylation of retinoblastoma (Rb), a master switch for cell cycle re-entry. Our findings show that the stabilization of neuronal primary cilia inhibits apop...

凋亡神经元的失败性细胞周期（Abortive cell cycle, ACC）重进入是近年来被阐明的一种现象，该现象发生于中枢神经系统（CNS）损伤后或中枢神经系统疾病进程中。因此，抑制细胞周期进程在多种中枢神经系统病理模型中均具有神经保护作用。初级纤毛（Primary cilia）是一类广泛存在、基于中心粒的细胞器，其功能为抑制细胞周期，但目前尚未有研究阐明其调控失败性细胞周期的能力。本研究证实，体外缺氧损伤与体内视神经横断（ONT）损伤均可导致神经元纤毛丢失。进一步实验发现，主动诱导纤毛吸收会使神经元对上述损伤更为敏感，并加剧细胞死亡。与之相反，通过药物抑制或短发夹RNA（shRNA）敲低纤毛解聚相关蛋白，可提升神经元存活率，并降低细胞周期重进入的关键开关——成视网膜细胞瘤蛋白（Rb）的磷酸化水平。我们的研究结果表明，稳定神经元初级纤毛可抑制凋亡...