Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390-8813, USA.
Exp Neurol. 2012 Oct;237(2):370-8. doi: 10.1016/j.expneurol.2012.07.009. Epub 2012 Jul 24.
Severed axons in adult mammals do not regenerate appreciably after central nervous system (CNS) injury due to developmentally determined reductions in neuron-intrinsic growth capacity and extracellular environment for axon elongation. Chondroitin sulfate proteoglycans (CSPGs), which are generated by reactive scar tissues, are particularly potent contributors to the growth-limiting environment in mature CNS. Thus, surmounting the strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcoming inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC (ChABC), but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed in order to develop more effective therapies to overcome CSPG-mediated inhibition of axon regeneration and/or sprouting. Because of their large size and dense negative charges, CSPGs were thought to act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ (PTPσ) and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3). If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries, including spinal cord injury (SCI).
成年哺乳动物的中枢神经系统 (CNS) 损伤后，轴突不会明显再生，这是由于神经元内在生长能力和轴突伸长的细胞外环境在发育过程中降低所致。软骨素硫酸盐蛋白聚糖 (CSPGs) 是由反应性瘢痕组织产生的，是成熟 CNS 中限制生长的环境的特别有力的贡献者。因此，克服富含 CSPG 的瘢痕的强烈抑制作用是实现 CNS 损伤后功能恢复的重要治疗目标。到目前为止，克服 CSPG 抑制作用的主要体内方法是用局部应用的软骨素酶 ABC（ChABC）进行酶消化，但由于这种细菌酶可能存在一些缺点，因此无法将其作为患者的治疗选择。为了开发更有效的治疗方法来克服 CSPG 介导的轴突再生和/或发芽抑制作用，需要更好地了解 CSPG 作用的分子机制。由于其体积大和带负电荷密度高，CSPGs 被认为通过空间位阻相互作用非特异性地阻碍基质分子与其细胞表面受体的结合来发挥作用。尽管这可能是正确的，但最近的研究表明，白细胞共同抗原相关 (LAR) 磷酸酶亚家族的两个成员，蛋白酪氨酸磷酸酶 σ (PTPσ) 和 LAR，是具有高亲和力结合 CSPG 并介导 CSPG 抑制作用的功能性受体。CSPGs 也可能通过与髓鞘相关生长抑制剂的两个受体结合而发挥作用，即神经生长抑制因子受体 1 和 3（NgR1 和 NgR3）。如果得到证实，这将表明 CSPGs 具有多种抑制轴突生长的机制，使它们成为特别强大和难以治疗的靶点。CSPG 受体的鉴定不仅对于理解瘢痕介导的生长抑制很重要，而且对于开发新型和选择性治疗方法以促进 CNS 损伤后轴突发芽和/或再生，包括脊髓损伤 (SCI) 也很重要。
