Peng Xue-Qi, Li Yan-Zhong, Gu Chen, He Xuan-Cheng, Li Chang-Ping, Sun Yong-Quan, Du Hong-Zhen, Teng Zhao-Qian, Liu Chang-Mei
Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
Cell Death Dis. 2024 Dec 18;15(12):906. doi: 10.1038/s41419-024-07281-6.
Regeneration of injured central nervous system (CNS) axons is highly restricted, leading to permanent neurological deficits. The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells, plays critical roles in development, brain plasticity, and tissues regeneration. However, little is known about the role of Marcks in CNS axon regeneration. Here we show that Marcks overexpression promotes robust axon regeneration either before or after optic nerve crush, but insignificantly impacts neuronal survival. Notably, immunostaining and RNA sequencing demonstrate that Marcks overexpression does not affect known regeneration-associated genes and pathways. Furthermore, combining CNTF which activates the JAK-STAT3 pathway and Marcks overexpression further enhances axon regeneration. Finally, we demonstrate functionally essential effector domain (ED) of MARCKS has similar effects on inducing axon regeneration in RGCs. These results suggest that manipulating Marcks and its ED may become a therapeutic approach to promote axon regeneration after CNS injury.
受损中枢神经系统（CNS）轴突的再生受到高度限制，会导致永久性神经功能缺损。富含豆蔻酰化丙氨酸的蛋白激酶C底物（MARCKS）是一种与膜相关的蛋白激酶C（PKC）底物，在真核细胞中普遍表达，在发育、脑可塑性和组织再生中发挥关键作用。然而，关于Marcks在中枢神经系统轴突再生中的作用知之甚少。在此我们表明，视神经挤压前后，Marcks过表达均能促进强劲的轴突再生，但对神经元存活影响不显著。值得注意的是，免疫染色和RNA测序表明，Marcks过表达不影响已知的再生相关基因和通路。此外，联合使用激活JAK-STAT3通路的睫状神经营养因子（CNTF）和Marcks过表达可进一步增强轴突再生。最后，我们证明了MARCKS功能上必不可少的效应结构域（ED）对诱导视网膜神经节细胞（RGCs）轴突再生具有相似作用。这些结果表明，调控Marcks及其ED可能成为促进中枢神经系统损伤后轴突再生的一种治疗方法。
