Folate nutrition and blood-brain barrier dysfunction

Abstract

Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

Figure 2. Folate- and vitamin B₁₂-mediated one-carbon metabolism

One-carbon metabolism is required for the synthesis of purines, thymidylate and methionine. The hydroxymethyl group of serine is a major source of one-carbon units, which are generated in the mitochondria in the form of formate via SHMT2, or in the cytoplasm through the activity of SHMT1 or SHMT2α. Mitochondrial-derived formate can enter the cytoplasm and function as a one-carbon unit for folate metabolism. The synthesis of thymidylate occurs in the nucleus and mitochondria. At S phase, the enzymes of the thymidylate synthesis pathway undergo SUMO-dependent translocation to the nucleus. The remethylation of homocysteine to methionine by MTR requires vitamin B₁₂. The one carbon is labeled in “bold”. The “inset” shows the thymidylate synthesis cycle which involves the enzymes, SHMT1, SHMT2α, TYMS and DHFR. THF, tetrahydrofolate; DHF, dihydrofolate, MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; SHMT, serine hydroxymethyltransferase; DHFR, dihydrofolate reductase; TYMS, thymidylate synthase; MTHFD1, methyleneTHF dehydrogenase; AdoMet, S-adenosylmethionine; AdoHcy, S-adenosylhomocysteine.