Folate one-carbon metabolism (FOCM) comprises a set of cellular reactions that transfer one-carbon units for a number of downstream functions including nucleotide biosynthesis and methylation reactions. Use of supplemental folic acid (the synthetic form of folate) before and during early pregnancy can prevent NTDs and all women planning pregnancy are recommended to take a folic acid supplement. These findings implicate folate metabolism in neural tube closure and a major focus of our research is to understand the relationship between folate status and susceptibility to NTDs.
In previous work we:
- Identified the first mouse mutant in which NTDs were associated with abnormal folate metabolism and preventable by folic acid (Fleming and Copp, Science 1998).
- Found that cranial neural tube closure requires activity of the methylation cycle, that uses s-adenosylmethionine as methyl donor (Dunlevy LP et al, FEBS Lett. 2006; Dunlevy et al, Birth Defects Res. A. 2006).
- Showed that dietary folate-deficiency causes NTDs only in genetically susceptible embryos in mice. These studies examined the correlation between maternal and embryonic folate status (Burren K et al, Hum. Mol. Genet. 2008; Burren et al, Birth Defects Res. A. 2010).
- Found that a proportion of human foetuses with NTDs exhibit a genetically-determined abnormality of folate metabolism (Dunlevy LP et al, Brain 2007).
- Identified mutations in genes encoding the glycine cleavage system (Gldc and Amt) that predispose to NTDs, showed these genes are also essential for neural tube closure in mice and identified abnormalities in FOCM (Narisawa et al, Hum. Mol. Genet. 2012; Pai YJ et al, Nat. Commun. 2015).
CURRENT WORK INCLUDES:
- Studies to determine how loss of function of glycine decarboxylase (Gldc) causes NTDs.
- Evaluating possible approaches for the prevention of folic acid-resistant NTDs. For example, we found that treatment with nucleotides (one of the products of folate metabolism) can prevent spina bifida in a folic acid-resistant mouse model (Leung KY et al, Brain 2013).
- Investigating the requirement for folate-dependent methylation in neural tube closure, using mass spectrometry-based metabolite analysis and epigenetic studies.
Analysis of folate metabolism in additional disease models and during normal development
As well as NTDs, abnormal FOCM is implicated in a number of other diseases including various cancers, fatty liver disease, inborn errors of metabolism, autism and age-related cognitive impairment.
- We are using a Gldc-deficient mouse model to investigate Non-Ketotic Hyperglycinemia (NKH).
- We collaborate on several studies examining the function of folate metabolism. For example, recent studies (i) analysed the metabolic effects of high levels of dietary folic acid (Christensen et al, Am J Clin Nutr 2015); (ii) determined the contribution of different enzymes to methylation in the early embryo (Zhang et al, FASEB J, 2015); (iii) investigated the mechanism by which bacteria modulate the effect of the drug metformin on C. elegans lifespan (Cabreiro et al., Cell, 2013).