Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
Department of Neurosurgery, Medical College of Wisconsin, VA Medical Center, Milwaukee, WI 53295, USA; Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montréal, QC H3G 1A4, Canada.
Neuron. 2017 Mar 8;93(5):1082-1093.e5. doi: 10.1016/j.neuron.2017.02.018.
Damaged central nervous system (CNS) neurons have a poor ability to spontaneously regenerate, causing persistent functional deficits after injury. Therapies that stimulate axon growth are needed to repair CNS damage. 14-3-3 adaptors are hub proteins that are attractive targets to manipulate cell signaling. We identify a positive role for 14-3-3s in axon growth and uncover a developmental regulation of the phosphorylation and function of 14-3-3s. We show that fusicoccin-A (FC-A), a small-molecule stabilizer of 14-3-3 protein-protein interactions, stimulates axon growth in vitro and regeneration in vivo. We show that FC-A stabilizes a complex between 14-3-3 and the stress response regulator GCN1, inducing GCN1 turnover and neurite outgrowth. These findings show that 14-3-3 adaptor protein complexes are druggable targets and identify a new class of small molecules that may be further optimized for the repair of CNS damage.
受损的中枢神经系统 (CNS) 神经元自身的再生能力很差，导致损伤后持续存在功能缺陷。需要能够刺激轴突生长的治疗方法来修复中枢神经系统损伤。14-3-3 衔接蛋白是衔接蛋白中的枢纽蛋白，是操纵细胞信号转导的有吸引力的靶点。我们确定了 14-3-3s 在轴突生长中的积极作用，并揭示了 14-3-3s 的磷酸化和功能的发育调控。我们表明，福司可林-A（FC-A），一种稳定 14-3-3 蛋白-蛋白相互作用的小分子，可刺激体外轴突生长和体内再生。我们表明，FC-A 稳定了 14-3-3 和应激反应调节剂 GCN1 之间的复合物，诱导 GCN1 周转和神经突生长。这些发现表明，14-3-3 衔接蛋白复合物是可成药的靶点，并确定了一类新的小分子，它们可能进一步优化用于中枢神经系统损伤的修复。
