PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration
PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration
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DOI：
10.1038/nn1193
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发表时间：
2004-03-01
影响因子：
25
通讯作者：
He, ZG
中科院分区：
文献类型：
--
作者：
Sivasankaran, R;Pei, J;He, ZG
哺乳动物中枢神经系统（CNS）中成功的轴突再生至少部分地由于与髓鞘和胶质瘢痕相关的抑制剂而受到损害。然而，这些抑制活性的细胞内信号传导机制在很大程度上是未知的。在这里，我们提供的生化和功能的证据表明，传统的蛋白激酶C（PKC）的亚型是介导髓鞘成分和硫酸软骨素蛋白聚糖（CSPGs），在胶质瘢痕的主要类别的抑制剂的抑制活性的信号转导通路的关键组成部分。髓鞘抑制剂和CSPGs均诱导PKC活化。阻断PKC活性可在遗传上减弱CNS髓鞘和CSPG激活Rho和抑制神经突生长的能力。鞘内注入PKC抑制剂，Go6976，到网站的背半切促进再生的背柱轴突跨越和超越病变部位在成年大鼠。因此，干扰PKC活性可能是一种刺激脑和脊髓损伤后轴突再生的治疗方法。
Successful axon regeneration in the mammalian central nervous system (CNS) is at least partially compromised due to the inhibitors associated with myelin and glial scar. However, the intracellular signaling mechanisms underlying these inhibitory activities are largely unknown. Here we provide biochemical and functional evidence that conventional isoforms of protein kinase C (PKC) are key components in the signaling pathways that mediate the inhibitory activities of myelin components and chondroitin sulfate proteoglycans (CSPGs), the major class of inhibitors in the glial scar. Both the myelin inhibitors and CSPGs induce PKC activation. Blocking PKC activity pharmacologically and genetically attenuates the ability of CNS myelin and CSPGs to activate Rho and inhibit neurite outgrowth. Intrathecal infusion of a PKC inhibitor, Go6976, into the site of dorsal hemisection promotes regeneration of dorsal column axons across and beyond the lesion site in adult rats. Thus, perturbing PKC activity could represent a therapeutic approach to stimulating axon regeneration after brain and spinal cord injuries.