Grant: Operating Grant

A sequence variant in an important enzyme of folate metabolism, methylenetetrahydrofolate reductase (MTHFR), increases risk for neural tube defects and may increase risk for several common diseases, including pregnancy complications and neuropsychiatric disorders. MTHFR is critical because it generates methyl donors for methylation reactions. The common variant is present in 5 to 20% of populations. We generated MTHFR-deficient mice to study complex disorders and identify ways to prevent or treat these common conditions. A second important goal is to evaluate the potential deleterious effects of high dietary folate since North Americans are ingesting much more folate following food fortification with folic acid and the extensive use of vitamin supplements. In recent studies with mutant mice, we identified motor and cognitive impairments with disturbances in metabolism of choline, an alternate methyl donor when folate is deficient. In folate-deficient mice, we observed lipid disturbances in liver which may also relate to decreased choline; these abnormalities can lead to fatty liver disease. We have shown that female mice that consume high levels of folate during pregnancy have delayed embryos, embryos with heart defects, and neonatal pups with cognitive impairment. In this application, we shall determine whether MTHFR deficiency in mice fed different diets (control, low folate, high fat) leads to liver disease. We shall also examine the impact of MTHFR deficiency and low folate or high folate diets during pregnancy on brain development in young pups. The mechanisms for these processes will be assessed by histological analyses, metabolite measurements, gene expression studies, and behavioural testing. We shall attempt to ameliorate negative outcomes with choline supplementation, since deficiency of this nutrient appears to contribute to liver and brain dysfunction.