Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKα Activity

Scientific Reports
Qinjie WengQiaojun He

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.

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Citations

Jul 31, 2018·Journal of Biomolecular Structure & Dynamics·Li Ting SongHong Lin Zhai
Sep 4, 2020·Nutrients·Matilde RodaCostantino Schiavi
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Dec 10, 2019·Journal of the Neurological Sciences·Luis E Almaguer-MederosPatrick MacLeod
May 22, 2021·Journal of Neuroendocrinology·Savani Anbalagan
Aug 10, 2021·Frontiers in Cell and Developmental Biology·Ethan G Hughes, Michael E Stockton
Aug 28, 2021·Journal of Personalized Medicine·Natasha Bobrowski-KhouryEdward V Quadros
Nov 12, 2021·The Journal of Medical Investigation : JMI·Shuhai ChenMitsuo Shimada

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Methods Mentioned

BETA
electron microscopy
ELISA
PCR

Software Mentioned

Image J

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