An epigenetic role for ascorbic acid in neurodegenerative diseases

I enjoyed reading the article by Moretti and coworkers1 in which they reviewed the preventive and therapeutic potential of ascorbic acid (vitamin C) in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, and multiple sclerosis. The authors discussed the neuromodulatory functions and antioxidant effects of ascorbic acid in relation to synaptic activation and neuronal metabolism. They referred to several studies that have indicated an association between low ascorbic acid levels and neurodegeneration. They mentioned that ascorbic acid acts mainly by decreasing oxidative stress and the formation of protein aggregates, effects which could contribute to the reduction of cognitive and/or motor impairments seen in neurodegenerative disorders. The authors also cited several studies that support a possible role for ascorbic acid in preventing and treating neurodegenerative diseases.

I wish to discuss the potential role of the epigenetic effects of ascorbic acid in neurodegenerative diseases. Epigenetics (above or in addition to genetics) is presently an active area of biomedical research. It involves the study of changes in gene expression not involving changes in DNA sequence. Epigenetics involves molecular mechanisms such as DNA methylation, DNA hydroxymethylation, histone modifications, and noncoding RNA‐mediated regulation of gene expression.2 Regarding DNA methylation, it occurs due to the conversion of cytosine to 5‐methylcytosine (5mC) by the addition of a methyl group. This reaction is catalyzed by DNA methyltransferases using S‐adenosylmethionine as the source of the methyl group. There is increasing evidence that epigenetic mechanisms of gene expression are involved in the development of neurodegenerative diseases.3, 4

In recent years, ascorbic acid has been found to have a role in epigenetic mechanisms of gene expression.5 In 2013, several groups showed that ascorbic acid serves as a cofactor for the ten‐eleven‐ten translocation (TET) dioxygenases.6, 7, 8, 9 These enzymes catalyze the oxidation of 5mC to 5‐hydroxymethylcytosine (5hmC), and then to 5‐formylcytosine (5fC) and 5‐carboxylcytosine (5caC).5 Abnormalities in the concentrations and/or activities of 5mC and 5hmC in the brain have been implicated in the development of neurodegenerative diseases.4, 10 As ascorbic acid is associated with 5mC and 5hmC, abnormalities in the concentration and/or activity of ascorbic acid in the brain could be associated with the development of these diseases. I suggest that in addition to the ways by which ascorbic acid may be associated with neurodegenerative diseases suggested by Moretti et al,1 ascorbic acid could also be associated epigenetically with the development of neurodegenerative diseases.