Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKα Activity.

Abstract

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.

• Authors: Qinjie Weng, Jiajia Wang, Jiaying Wang, Biqin Tan, Jing Wang, Haibo Wang, Tao Zheng, Q Richard Lu, Bo Yang, Qiaojun He
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 1705 (05 11 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28496133 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Folic Acid Antagonists
• Folic Acid
• Tetrahydrofolate Dehydrogenase
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Animals
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Folic Acid (metabolism)
• Folic Acid Antagonists (pharmacology)
• Mice, Inbred C57BL
• Myelin Sheath (metabolism)
• Oligodendroglia (enzymology, metabolism, pathology)
• Optic Nerve (pathology, ultrastructure)
• Phosphorylation (drug effects)
• Spinal Cord (pathology, ultrastructure)
• Tetrahydrofolate Dehydrogenase (metabolism)