Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest 2010 May;120(5):1603-16
Date
04/29/2010Pubmed ID
20424322Pubmed Central ID
PMC2860927DOI
10.1172/JCI40000Scopus ID
2-s2.0-77951810285 (requires institutional sign-in at Scopus site) 127 CitationsAbstract
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.
Author List
Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, Jarrard DF, Banerjee RV, Skene JH, Nelson A, Patel N, Gherasim C, Simon K, Cook TD, Hogan KJAuthor
Kathleen L. Lak MD Associate Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAxons
Brain
Central Nervous System
DNA Methylation
DNA Modification Methylases
Folic Acid
Humans
In Situ Hybridization
Male
Mice
Models, Biological
Nerve Regeneration
Rats
Rats, Sprague-Dawley
Spinal Cord
Tetrahydrofolate Dehydrogenase
