Nerve Regeneration Group, Program in Neurobiology and Neurologic Disorders, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, and.
Graduate Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
J Clin Invest. 2020 Apr 1;130(4):2024-2040. doi: 10.1172/JCI125771.
After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there is no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator of actin and microtubules (MTs), powering axonal growth and regeneration. In growth cones, Pfn1 increased actin retrograde flow, MT growth speed, and invasion of filopodia by MTs, orchestrating cytoskeletal dynamics toward axonal growth. In vitro, active Pfn1 promoted MT growth in a formin-dependent manner, whereas localization of MTs to growth cone filopodia was facilitated by direct MT binding and interaction with formins. In vivo, Pfn1 ablation limited regeneration of growth-competent axons after sciatic nerve and spinal cord injury. Adeno-associated viral (AAV) delivery of constitutively active Pfn1 to rodents promoted axonal regeneration, neuromuscular junction maturation, and functional recovery of injured sciatic nerves, and increased the ability of regenerating axons to penetrate the inhibitory spinal cord glial scar. Thus, we identify Pfn1 as an important regulator of axonal regeneration and suggest that AAV-mediated delivery of constitutively active Pfn1, together with the identification of modulators of Pfn1 activity, should be considered to treat the injured nervous system.
创伤后，成人中枢神经系统轴突的再生是夭折的，导致毁灭性的神经功能缺损。尽管康复护理取得了进展，但仍没有有效的治疗方法能在损伤后刺激轴突生长。我们使用具有不同再生能力的模型，进行增益和缺失功能分析，确定了 Profilin 1（Pfn1）是一种协调肌动蛋白和微管（MTs）的蛋白，为轴突生长和再生提供动力。在生长锥中，Pfn1 增加了肌动蛋白的逆行流动、MT 的生长速度和 MT 对丝状伪足的入侵，协调细胞骨架向轴突生长的动力学。在体外，活性 Pfn1 以formin 依赖性的方式促进 MT 的生长，而 MT 定位到生长锥的丝状伪足则是通过直接的 MT 结合和与formin 的相互作用来促进的。在体内，Pfn1 的缺失限制了坐骨神经和脊髓损伤后有生长能力的轴突的再生。腺相关病毒（AAV）向啮齿动物传递组成性激活的 Pfn1 可促进轴突再生、运动终板成熟以及损伤的坐骨神经的功能恢复，并增加再生轴突穿透抑制性脊髓神经胶质瘢痕的能力。因此，我们确定 Pfn1 是轴突再生的一个重要调节因子，并表明 AAV 介导的组成性激活 Pfn1 的传递，以及 Pfn1 活性调节剂的鉴定，应被考虑用于治疗受损的神经系统。
