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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Iskandar, BJ; Rizk, E; Meier, B; Hariharan, N; Bottiglieri, T; Finnell, RH; Jarrard, DF; Banerjee, RV; Skene, JHP; Nelson, A; Patel, N; Gherasim, C; Simon, K; Cook, TD; Hogan, KJ

Published Date

  • May 2010

Published In

Volume / Issue

  • 120 / 5

Start / End Page

  • 1603 - 1616

PubMed ID

  • 20424322

Pubmed Central ID

  • 20424322

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI40000


  • eng

Conference Location

  • United States