Abstract

2007). Thus, the ability for folates to methylate homocysteine to its nontoxic derivative methionine plays a large role in protecting against neurotoxicity. However, the links between these illnesses and homocysteine are still not fully understood, with many downstream biochemical pathways still needing to be discovered. Research into increased homocysteine levels and altered folate metabolism confirms a variety of cytotoxic effects in Caenorhabditis elegans (Ortbauer et al., 2016), Drosophila melanogaster (Blatch, Stabler & Harrison, 2015) and Sacchaomyces cerevisiae (Kumar et al., 2011). Thus, the need to utilize mammal models of increased levels of homocysteine is necessary to produce potential theories of illness. One such model looks at the knockout of a particular enzyme in the homocysteine cycle, known as methylenetetrahydrofolate reductase (MTHFR). Folate itself cannot directly methylate homocysteine, thus it must first be converted from the form it is ingested to its primary circulating form, 5-methyltetrahydrofolate (5-methyl-THF). The key enzyme to this process is the aforementioned MTHFR, which catalyzes the production of 5-methyl-THF from a less abundant form 5,10-methyl-THF, which then methylates homocysteine. Thus, this enzyme is essential to both the metabolism of folate and homocysteine. This cycle is highlighted in Figure 1. The occurrence of MTHFR deficiency is not uncommon in humans, with two common mutations producing reduced or lack of function. One of these deficiency-causing mutations is homozygous in approximately 18 percent of humans (Zittan et al., 2007). As many as 34 mutations in this gene, however, have been identified in individuals with homocystinuria, a genetic condition resulting in elevated levels of homocysteine that is associated with neurological and vascular problems (Leclerc, Sibani & Rozen, 2000). INTRODUCTION Folate metabolism is a key mechanism in the brain that allows the downstream alteration of a variety of proteins and plays a role in the synthesis of nucleotides (Kamen, 1997). These folatemediated effects are necessary for the production of new neural cells and thus are essential to the overall health of the brain during development, adulthood and aging (McGarel, Pentieva, Strain & McNulty, 2015). One mechanism through which folates affect protein function is through the initial methylation of homocysteine to methionine. Homocysteine is a cytotoxic molecule when in high levels that produces a variety of negative effects, including endoplasmic reticulum stress, excitatory amino acid receptor overactivation, kinase hyperactivity and DNA damage (Ho, Ortiz, Rogers & Shea, 2002). These effects have been associated with many clinical pathologies in humans, being indicated as a contributing factor to cognitive impairment (Almeida et al., 2005), neural tube defects (Felkner, Suarez, Canfield, Brender & Sun, 2009), brain atrophy (den Heijer et al., 2003), stroke (Hankey & Eikelboom, 2001) and cardiovascular disease (Frosst et al., 1995; Wierzbicki, Neurogenesis Unchanged by MTHFR Deficiency in Three-Week-Old Mice