Regulatory Mechanisms of Folate Transporters by Transcription Factors in the Brain

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Folates (Vit B9) are water soluble vitamins required for key biosynthetic processes in mammalian cells. Folate transport across biological membranes and tissues is mediated by three major pathways: folate receptor alpha (FRa), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). The functional expression of these folate transport pathways can be regulated by several transcription factors such as the Vitamin D receptor (VDR). Folates are critical for brain development and function. Inactivation of FRa, the major folate transport pathway at the blood-cerebrospinal fluid barrier, through loss-of-function mutations or the presence of FRa autoantibodies, causes severe cerebral folate deficiency characterized by inflammation, oxidative stress, mitochondrial dysfunction and abnormal brain myelination. Recently, as part of the NSERC grant approved in April 2015, we demonstrated that modulating folate uptake at the blood-brain barrier (BBB) through induction of specific folate transporters (i.e., RFC) could present a novel strategy for enhancing brain folate delivery in the context of defective FRa. We provided evidence that activation of VDR through exposure to its activating ligand, 1,25-dihydroxyvitamin D3 (calcitriol), induced RFC function at the BBB and effectively restored folate levels in the brain of mice lacking FRa. Although these results are very exciting, we observed that the animals treated with calcitriol presented toxicities such as weight loss and high calcium blood levels. NRF-1 is a transcription factor primarily known for its role in promoting mitochondrial and respiratory function. We recently determined that it can also regulate the folate transporter, RFC at the BBB. We propose that, in the context of defective FRa in the brain, activation of NRF-1 by its specific ligand, pyrroloquinoline quinone (PQQ), a natural non-toxic compound, can enhance RFC function and increase folate delivery into the brain reversing inflammation, oxidative stress, as well as mitochondrial dysfunction. Our proposed work will uncover fundamental mechanisms involved in mitochondrial dysfunction, brain inflammation and oxidative stress related to cerebral folate deficiency, elucidate how these effects can be reversed when brain folate levels are restored, and provide novel treatment approaches for neurometabolic disorders caused by loss of FRa function. Further, the findings of this project present broader applications due to the growing body of evidence associating mitochondrial dysfunction to neurological disorders and may also be exploited as a novel delivery route for several pharmacological agents known to have very poor CNS permeability (i.e., anticancer drugs). With the undertaking of the proposed work, we plan to train and mentor highly qualified personnel to become future leaders in the natural sciences.