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Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation
Bermans J. Iskandar, … , Thomas D. Cook, Kirk J. Hogan
Bermans J. Iskandar, … , Thomas D. Cook, Kirk J. Hogan
Published April 26, 2010
Citation Information: J Clin Invest. 2010;120(5):1603-1616. https://doi.org/10.1172/JCI40000.
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Research Article Article has an altmetric score of 4

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

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Abstract

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.

Authors

Bermans J. Iskandar, Elias Rizk, Brenton Meier, Nithya Hariharan, Teodoro Bottiglieri, Richard H. Finnell, David F. Jarrard, Ruma V. Banerjee, J.H. Pate Skene, Aaron Nelson, Nirav Patel, Carmen Gherasim, Kathleen Simon, Thomas D. Cook, Kirk J. Hogan

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Figure 9

Global DNA methylation in the injured spinal cord follows a biphasic curve in response to increasing doses of FA.

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Global DNA methylation in the injured spinal cord follows a biphasic cur...
This curve corresponds to the biphasic Dnmt and Folr1 protein levels as well as the spinal regeneration response. We measured global methylation in the spinal cords of animals with combined spinal cord and peripheral nerve injuries, which were subjected to varying doses of i.p. FA given daily starting 3 days prior to the injury and continuing 4 days. n = 12 (uninjured control animals); n (FA dose) = 32 (0 μg/kg); 33 (20 μg/kg); 32 (40 μg/kg); 33 (80 μg/kg); 34 (160 μg/kg); 32 (400 μg/kg); 32 (800 μg/kg). The quadratic term in the dose-response model was statistically significant (P = 0.001), confirming that there is a U-shaped dose response to the folate dose on a log scale. There are no differences between the injured/untreated animals and the animals treated with 20 μg/kg FA (P = 0.99), nor between the animals treated with the 400 μg/kg and 800 μg/kg doses (P = 0.85). Note the tight correlation in the biphasic FA dose effects between global DNA methylation, spinal regeneration (Figure 7F), and the Dnmt3a and Dnmt3b as well as Folr1 protein levels (Figure 7, A–C, and E). The FA dose of 80 μg/kg, at which both DNA methylation and Dnmt3a and Dnmt3b and Folr1 expression levels were maximal, was found to be the most effective in promoting regeneration.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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