Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Center for drug safety Evaluation and Research, Zhejiang University, Hangzhou, China.
Sci Rep. 2017 May 11;7(1):1705. doi: 10.1038/s41598-017-01732-1.
Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism for many cellular pathways including DNA synthesis, metabolism and maintenance. Folate deficiency has been associated with an increased risk of neurological disease, cancer and cognitive dysfunction. Dihydrofolate reductase (DHFR) is a key enzyme to regulate folate metabolism, however folate/DHFR activity in oligodendrocyte development has not been fully understood. Here we show that folate enhances oligodendrocyte maturation both in vitro and in vivo, which is accompanied with upregulation of oligodendrocyte-specific DHFR expression. On the other hand, pharmacological inhibition of DHFR by methotrexate (MTX) causes severe defects in oligodendrocyte survival and differentiation, which could be reversed by folate intake. We further demonstrate that folate activates a metabolic regulator AMPKα to promote oligodendrocyte survival and differentiation. Moreover, activation of AMPKα partially rescues oligodendrocyte defects caused by DHFR-inhibition both in vitro and in vivo. Taken together, these findings identify a previously uncharacterized role of folate/DHFR/AMPKα axis in regulating oligodendrocyte survival and myelination during CNS development.
叶酸是一种必需的微量营养素，是许多细胞途径中一碳代谢的关键辅助因子，包括 DNA 合成、代谢和维持。叶酸缺乏与神经疾病、癌症和认知功能障碍的风险增加有关。二氢叶酸还原酶（DHFR）是调节叶酸代谢的关键酶，然而，少突胶质细胞发育中的叶酸/DHFR 活性尚未完全理解。在这里，我们表明叶酸在体外和体内均增强少突胶质细胞成熟，这伴随着少突胶质细胞特异性 DHFR 表达的上调。另一方面，二氢叶酸还原酶的药理学抑制剂甲氨蝶呤（MTX）导致少突胶质细胞存活和分化严重缺陷，这可以通过叶酸摄入来逆转。我们进一步证明，叶酸激活代谢调节剂 AMPKα 以促进少突胶质细胞存活和分化。此外，在体外和体内，AMPKα 的激活部分挽救了由 DHFR 抑制引起的少突胶质细胞缺陷。总之，这些发现确定了叶酸/DHFR/AMPKα 轴在调节中枢神经系统发育过程中少突胶质细胞存活和髓鞘形成中的一个以前未被描述的作用。
