Cafferty William B J, Yang Shih-Hung, Duffy Philip J, Li Shuxin, Strittmatter Stephen M
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Neurosci. 2007 Feb 28;27(9):2176-85. doi: 10.1523/JNEUROSCI.5176-06.2007.
Axotomized neurons within the damaged CNS are thought to be prevented from functional regeneration by inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors. Here, we provide a transgenic test of the role of CSPGs in limiting regeneration, using the gfap promotor to express a CSPG-degrading enzyme chondroitinase ABC (ChABC) in astrocytes. Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice. The presence of the gfap-ChABC transgene yields no significant improvement in motor function recovery in this model. In contrast, functionally significant sensory axon regeneration is observed after dorsal rhizotomy in transgenic mice. These transgenic studies confirm a local efficacy for reduced CSPG to enhance CNS axon growth after traumatic injury. CSPGs appear to function in a spatially distinct role from myelin inhibitors, implying that combination-based therapy will be especially advantageous for CNS injuries.
受损中枢神经系统内的轴突切断神经元被认为会受到诸如硫酸软骨素蛋白聚糖（CSPG）和髓磷脂相关抑制剂等抑制分子的阻碍而无法进行功能再生。在此，我们利用胶质纤维酸性蛋白（gfap）启动子在星形胶质细胞中表达一种CSPG降解酶硫酸软骨素酶ABC（ChABC），对CSPG在限制再生中的作用进行了转基因测试。在转基因小鼠进行背侧半切术后，皮质脊髓轴突在损伤部位内延伸，但在损伤部位尾侧则不延伸。gfap-ChABC转基因的存在在该模型中并未使运动功能恢复有显著改善。相比之下，在转基因小鼠进行背根切断术后观察到了具有功能意义的感觉轴突再生。这些转基因研究证实了降低CSPG对增强创伤性损伤后中枢神经系统轴突生长具有局部有效性。CSPG似乎在空间上发挥着与髓磷脂抑制剂不同的作用，这意味着基于联合的疗法对中枢神经系统损伤将特别有利。
