From the Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK University Medical Center, Edison, New Jersey.
Department of Neurology, Hackensack Meridian School of Medicine, Nutley, New Jersey.
J Neuropathol Exp Neurol. 2021 Jan 20;80(2):169-181. doi: 10.1093/jnen/nlaa147.
The long-term disabilities associated with spinal cord injury (SCI) are primarily due to the absence of robust neuronal regeneration and functional plasticity. The inability of the axon to regenerate after SCI is contributed by several intrinsic factors that trigger a cascade of molecular growth program and modulates axonal sprouting. Phosphatase and tensin homolog (PTEN) is one of the intrinsic factors contributing to growth failure after SCI, however, the underlying mechanism is not well known. Here, we developed a novel therapeutic approach for treating SCI by suppressing the action of PTEN in a mouse model of hemisection SCI. We have used a novel peptide, PTEN antagonistic peptide (PAP) to block the critical domains of PTEN to demonstrate its ability to potentially promote axon growth. PAP treatment not only enhanced regeneration of corticospinal axons into the caudal spinal cord but also promoted the regrowth of descending serotonergic axons in SCI mice. Furthermore, expression levels of p-mTOR, p-S6, p-Akt, p-Erk, p-GSK, p-PI3K downstream of PTEN signaling pathway were increased significantly in the spinal cord of SCI mice systemically treated with PAP than control TAT peptide-treated mice. Our novel strategy of administering deliverable compounds postinjury may facilitate translational feasibility for central nervous system injury.
脊髓损伤（SCI）相关的长期残疾主要是由于缺乏强大的神经元再生和功能可塑性。SCI 后轴突无法再生是由几个内在因素引起的，这些因素引发了一系列分子生长程序，并调节轴突发芽。磷酸酶和张力蛋白同源物（PTEN）是导致 SCI 后生长失败的内在因素之一，然而，其潜在机制尚不清楚。在这里，我们通过在 SCI 横断模型的小鼠中抑制 PTEN 的作用，开发了一种治疗 SCI 的新疗法。我们使用了一种新型肽，PTEN 拮抗肽（PAP）来阻断 PTEN 的关键结构域，以证明其促进轴突生长的潜力。PAP 治疗不仅增强了皮质脊髓轴突向脊髓尾部的再生，而且促进了 SCI 小鼠下行 5-羟色胺能轴突的再生长。此外，与对照组 TAT 肽处理的小鼠相比，用 PAP 全身性治疗的 SCI 小鼠脊髓中 PTEN 信号通路的下游 p-mTOR、p-S6、p-Akt、p-Erk、p-GSK 和 p-PI3K 的表达水平显著增加。我们在损伤后给予可传递化合物的新策略可能为中枢神经系统损伤的转化可行性提供便利。
