Regulation of Low-Affinity Folate Transporters in the Brain

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Folates are water soluble vitamins that play a critical role in tissue development, function and repair. Humans must obtain folate from their diet since they cannot synthesize it from other nutrients. Folate deficiency is one of the major dietary health problems worldwide and is associated with significant disturbances that affect tissues such as bone marrow, intestine and developing brain. Folates being negatively charged water soluble molecules at physiological pH cross biological membranes very poorly by diffusion and thus need specific membrane carriers (transporters) for intestinal uptake and to gain access to vital organs such as the brain. A number of folate transporters have been identified in several tissues including the intestine, kidney and brain. In particular, the folate receptors alpha (FRa) constitutes a major transport pathway in the brain. Folate transport is critical for the maintenance of normal brain function. FRa mutations and/or presence of antibodies against this receptor can cause severe folate deficiency and result in childhood neurodegeneration. To date, folate transport in the brain has been largely investigated through the FRa; however, little is known on the properties of other folate transporters in the brain. Apart from the FRa, there are at least two other transport systems for folates, which have lower affinity for folates compared to FRa, i.e. require higher folate concentrations. In the intestine, folate transport is mediated by the proton-coupled folate transporter (PCFT) which functions optimally at acidic pH. The reduced folate carrier (RFC) is another low affinity folate transporter which exchanges folate with other inorganic or organic anions. At present, the contribution of these transporters to the overall brain folate uptake remains unclear. Recent studies report that PCFT and RFC can be regulated by nuclear receptors, in particular, the vitamin D receptor (VDR). We propose that in the context of FRa mutations and/or presence of FRa antibodies which render this mechanism of folate transport ineffective, the low affinity folate transporters could play a significant role in brain folate uptake. Furthermore, the induction of the same transporters may provide alternative routes for effective folate penetration into the brain. The objectives of this proposal are to investigate the contribution of the low affinity folate transporters, PCTF and RFC, in folate uptake by several brain cellular models and to examine the role of nuclear receptors i.e., VDR, in folate transporter regulation using animal mouse models lacking FRa. It is anticipated that an induction of the folate transporters i.e., PCFT, through administration of specific VDR ligands will result in an enhanced brain uptake of folate derivatives. This work could uncover novel strategies for the treatment of brain disorders caused by folic acid deficiency.