Li Heng, Wong Connie, Li Wen, Ruven Carolin, He Liumin, Wu Xiaoli, Lang Bradley T, Silver Jerry, Wu Wutian
School of Biomedical Sciences, Division of Anatomy, the University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
Department of Neurosciences, Case Western Reserve University School of Medicine, 2109 Adelbert Road Cleveland, OH 44106, USA.
Sci Rep. 2015 Oct 14;5:14923. doi: 10.1038/srep14923.
Following root avulsion, spinal nerves are physically disconnected from the spinal cord. Severe motoneuron death and inefficient axon regeneration often result in devastating motor dysfunction. Newly formed axons need to extend through inhibitory scar tissue at the CNS-PNS transitional zone before entering into a pro-regenerative peripheral nerve trajectory. CSPGs are dominant suppressors in scar tissue and exert inhibition via neuronal receptors including PTPσ. Previously, a small peptide memetic of the PTPσ wedge region named ISP (Intracellular Sigma Peptide) was generated, and its capabilities to target PTPσ and relieve CSPG inhibition were validated. Here, we demonstrate that after ventral root avulsion and immediate re-implantation, modulation of PTPσ by systemic delivery of ISP remarkably enhanced regeneration. ISP treatment reduced motoneuron death, increased the number of axons regenerating across scar tissue, rebuilt healthy neuromuscular junctions and enhanced motor functional recovery. Our study shows that modulation of PTPσ is a potential therapeutic strategy for root avulsion.
神经根撕脱后，脊神经与脊髓在物理上断开连接。严重的运动神经元死亡和低效的轴突再生常常导致严重的运动功能障碍。新形成的轴突在进入促进再生的周围神经轨迹之前，需要穿过中枢神经系统-周围神经系统过渡区的抑制性瘢痕组织。硫酸软骨素蛋白聚糖（CSPGs）是瘢痕组织中的主要抑制因子，并通过包括蛋白酪氨酸磷酸酶σ（PTPσ）在内的神经元受体发挥抑制作用。此前，人们制备了一种名为ISP（细胞内σ肽）的、模拟PTPσ楔形区域的小肽，并验证了其靶向PTPσ和减轻CSPG抑制的能力。在此，我们证明，在腹侧神经根撕脱并立即重新植入后，通过全身递送ISP对PTPσ进行调节可显著增强再生。ISP治疗减少了运动神经元死亡，增加了穿过瘢痕组织再生的轴突数量，重建了健康的神经肌肉接头，并增强了运动功能恢复。我们的研究表明，调节PTPσ是一种治疗神经根撕脱的潜在策略。
