Neuronal injury: folate to the rescue?

Abstract

Strong epidemiological evidence indicates that derangement of single-carbon metabolism has detrimental effects for proper CNS functioning. Conversely, a role for folate supplementation in the treatment and prevention of neurodegenerative and neuropsychiatric disorders remains to be established. In this issue of the JCI, in an elegant series of experiments in rodents, Iskandar and colleagues demonstrate a crucial role of folate in the regeneration of afferent spinal neurons after injury. Probing sequential steps in folate metabolism, from cellular entry to DNA methylation, the authors show that axonal regeneration relies upon the integrity of DNA methylation pathways. These findings provide the first demonstration of an epigenetic mechanism contributing to neurorepair and suggest that manipulation of the methylation milieu may offer promising new therapeutic avenues to promote regeneration.

Figure 1. Role of folate in axonal regeneration.

The figure summarizes the sequence of events reported in this issue of the JCI by Iskandar et al. (7) that underlie the proregenerative effects of folate on injured CNS tissue in their rodent models. Experimental manipulations that can block this pathway at specific steps are shown on the left. Following transection injury to the CNS, increased expression of FOLR1 promotes folate uptake. Folate is then reduced to tetrahydrofolate (THF) by DHFR. Methyl-THF is required for the regeneration of SAM, which in turn promotes methylation of spinal cord DNA. Sufficient DNA methylation is crucial for axonal regeneration. 5-AzaC, 5-azacytidine.