Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA.
J Clin Invest. 2010 May;120(5):1603-16. doi: 10.1172/JCI40000. Epub 2010 Apr 26.
The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.
叶酸代谢途径在成年中枢神经系统（CNS）损伤后的再生和修复中起着至关重要的作用。在这里，我们在啮齿动物中表明，这种修复至少部分是通过 DNA 甲基化实现的。在脊髓和坐骨神经联合损伤的动物中，发现叶酸介导的 CNS 轴突再生依赖于损伤相关的高亲和力叶酸受体 1（Folr1）的诱导。叶酸的活性取决于其被二氢叶酸还原酶（Dhfr）激活和功能性甲基化循环。叶酸对传入脊髓神经元再生的作用呈双相和剂量依赖性，并且在其剂量范围内与全局和基因特异性 DNA 甲基化以及叶酸受体 Folr1 和从头 DNA 甲基转移酶的表达密切相关。这些数据表明，表观遗传机制在 CNS 修复中起作用。因此，叶酸酸和可能的其他非毒性膳食甲基供体可能对促进大脑和脊髓愈合的临床干预有用。如果叶酸的益处确实是通过促进内源性轴突再生的表观遗传机制介导的，那么这为治疗 CNS 损伤的新的药物治疗方法提供了可能的途径。
