title: Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.
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.affiliation: Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA. iskandar@neurosurg.wisc.edu
authors.forename: Bermans J
authors.initials: BJ
authors.lastname: Iskandar
authors.forename: Elias
authors.initials: E
authors.lastname: Rizk
authors.forename: Brenton
authors.initials: B
authors.lastname: Meier
authors.forename: Nithya
authors.initials: N
authors.lastname: Hariharan
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
authors.forename: Ruma V
authors.initials: RV
authors.lastname: Banerjee
authors.forename: J H Pate
authors.initials: JH
authors.lastname: Skene
authors.forename: Aaron
authors.initials: A
authors.lastname: Nelson
authors.forename: Nirav
authors.initials: N
authors.lastname: Patel
authors.forename: Carmen
authors.initials: C
authors.lastname: Gherasim
authors.forename: Kathleen
authors.initials: K
authors.lastname: Simon
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Cook
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Hogan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008954:Models, Biological; D009416:Nerve Regeneration; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
chemical_list: D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D015254:DNA Modification Methylases