Cobalamin-related redox metabolic pathways in neuronal cells. Endocytosis brings TC-bound Cbl species to lysosomes where axial ligands are removed by MMACHC and MeCbl or AdoCbl are subsequently formed by SAM and ATP-dependent pathways, respectively. MeCbl is a required cofactor for methionine synthase, whose activity supports a large number of methylation reactions, including DNA methylation, as well as dopamine-stimulated phospholipid methylation, carried out by the D4 dopamine receptor (D4R). AdoCbl supports MMACoA mutase in mitochondria. Cysteine, which is rate-limiting for GSH synthesis, can be provided either by cellular uptake via the cysteine/glutamate transporter EAAT3 (excitatory amino acid transporter 3) or by transsulfuration of HCY via cystathionine. The latter pathway is restricted in human brain, increasing the importance of growth factor-dependent cysteine uptake by EAAT3.
A new study published in PLOS One found that Vitamin B12 levels in the brain are significantly decreased in the elderly and are much lower in individuals with autism or schizophrenia, as compared to their peers at similar ages. Eg. children with autism under the age of 10 were found to have 3X lower brain B12 levels, which is similar to levels for generally healthy adults in their 50s, indicating a premature decrease.
The international research team analyzed tissue from otherwise healthy deceased donors along with tissue from donors who had autism or schizophrenia to make the comparisons. “These are particularly significant findings because the differences we found in brain B12 with aging, autism and schizophrenia are not seen in the blood, which is where B12 levels are usually measured.” said Dr. Deth. “The large deficits of brain B12 from individuals with autism and schizophrenia could help explain why patients suffering from these disorders experience neurological and neuropsychiatric symptoms.”
Redox and methylation metabolites in aging and autism.
The study also found healthy elderly people 61-80yo have about 3X lower levels of total brain B12 than younger age groups, which is a result of normal aging. This normal decrease may help adjust brain metabolism to sustain its function across the lifespan.
An active form of B12 called methylcobalamin, or methyl B12, supports normal brain development by its control through a process known as epigenetic regulation of gene expression. Remarkably, the brain level of methyl B12 was found to be > 10X lower in healthy elderly people than in healthy younger people. A lower than normal level of methyl B12 in the brain could adversely affect neurodevelopment in younger years and could disrupt learning and memory later in life.
Both autism and schizophrenia are associated with oxidative stress, which also plays an important role in aging, and oxidative stress may underlie the decreased brain B12 levels observed in this study. The findings suggest the need for further research to determine if the use of supplemental methyl B12 and antioxidants like glutathione could help prevent oxidative stress and be useful in treating these conditions. http://www.newswise.com/articles/researchers-find-brain-levels-of-vitamin-b12-decrease-with-age-and-are-prematurely-low-in-people-with-autism-and-schizophrenia http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797
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