Dr. Richard Deth Explains Compelling New Research
Building upon a previous study which demonstrated that gene expression of B12 and folate-dependent enzyme methionine synthase was lower in individuals with autism, a new study has shown that oxidative stress (i.e. low antioxidant levels) and impaired methylation are telltale signs of autism. This research was included as part of a recently completed PhD thesis project of Dr. Matthew Schrier. Long time autism researcher, Dr. Richard Deth contributed to this important work.
SafeMinds reached out to Dr. Deth to receive a more complete picture of this research. He offered the following summary of the study:
In earlier studies of postmortem brain (frontal cortex) samples, our team found gene expression of the B12 and folate-dependent enzyme methionine synthase was lower in ASD subjects and methylB12 levels were lower. In this study, we first looked at the expression of genes that regulate the metabolic pathways related to glutathione production and found that several were low, including the gene that encodes for the transcription factor Nrf2 (the gene abbreviation is NFE2L2). Nrf2 is considered to be the master regulator of antioxidant production. As a transcription factor, it turns on hundreds of genes that together serve to improve antioxidant status in response to oxidative stress. However, we found that its own gene expression was low, which might help explain why glutathione levels are low in autism. For example, Nrf2 activity promotes absorption of cysteine from the GI tract by up-regulating expression of cysteine transport proteins. These same cysteine transporters are also found in neurons and in immune cells, so GI, immune and brain manifestations of low Nrf2 in autism make sense.
In our new study we also looked that the correlation between NFE2l2 expression (i.e. Nrf2 gene expression) and vitamin B12 (cobalamin or Cbl) status in brain samples. The cobalt atom in vitamin B12 is subject to oxidation, and it loses activity when it is oxidized. In addition, the processing of B12 in cells needs antioxidants. Thus oxidative stress from low activity of Nrf2 could also result in impaired vitamin B12 function. We found that tissue levels of oxidized B12 (OHCbl) were lower when NFE2L2 levels were higher, while levels of methylB12 were higher when NFE2L2 levels were higher. This confirms a relationship between antioxidant status (redox) and B12 status.
To further explore the relationship between B12 status and Nrf2 activity we also carried out an investigation of the relationship between Nrf2-induced gene expression and cobalamin levels in different human tissues, using levels reported in the literature. We found that tissues with higher levels of B12 (e.g. liver) had the higher levels of Nrf2 activity (i.e. more antioxidant) and vice versa, with the brain having the lowest B12 content and lowest Nrf2 activity.
The take home message is no surprise: Autism is associated with too few antioxidants and as a result B12-dependent methylation activity is impaired. Supporting cysteine and B12 levels would seem to make sense, which is, of course, already a familiar theme for many.
