Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.
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.
Iskandar
Bermans J
BJ
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA. iskandar@neurosurg.wisc.edu
Rizk
Elias
E
Meier
Brenton
B
Hariharan
Nithya
N
Bottiglieri
Teodoro
T
Finnell
Richard H
RH
Jarrard
David F
DF
Banerjee
Ruma V
RV
Skene
J H Pate
JH
Nelson
Aaron
A
Patel
Nirav
N
Gherasim
Carmen
C
Simon
Kathleen
K
Cook
Thomas D
TD
Hogan
Kirk J
KJ
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*
D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D015254:DNA Modification Methylases