Tetrahydrobiopterin May Be Transported into the Central Nervous System by the Folate Receptor α

Abstract: 

Richard E. Frye, MD, PhD*

The aim of this study was to determine if tetrahydrobiopterin (BH4), a cofactor that is essential for several critical neurometabolic pathways, is transported across the blood-brain barrier (BBB) using the same transport mechanism as folate. In this study we examined 30 children with ASD (mean age 7.5 years, standard deviation 3.2 years; 23% female). We studied autoantibodies that interfere with the binding of folate to the folate receptor α (FRα) – a receptor that is critically involved in the transport of folate across the BBB. The relationships between cerebrospinal fluid (CSF) BH4 concentrations with FRα autoantibody titers as well as with the interaction between CSF 5-methyltetrahydrofolate (5MTHF) concentration and FRα autoantibody titers were studied. CSF BH4 concentration was found to be lower in individuals with higher FRα blocking, but not binding, autoantibody serum titers, suggesting that interference with FRα dependent BBB transport interferes with BH4 transport across the BBB. This effect was not explained by lower CSF 5MTHF concentrations, thereby reducing the possibility that low CSF BH4 concentrations were secondary to low central folate. In addition, CSF BH4 concentration was inversely correlated with the interaction between CSF 5MTHF and FRα blocking autoantibody titers suggesting that BH4 competes with folate for FRα dependent transport across the BBB. These data suggest that FRα dependent transport mechanisms may be involved in the transportation of BH4 across the BBB.

Key Words: tetrahydrobiopterin, folate receptor alpha, autoantibodies, cerebrospinal fluid, autism

Richard E. Frye, MD, PhD*
Arkansas Children’s Hospital Research Institute, Little Rock, AR
*Corresponding Author: Arkansas Children’s Hospital Research Institute, Slot 512-41B, 13 Children’s Way, Little Rock, AR 72202. Tel: 501-364-4662.
(Email: REFrye@uams.edu)

CONFLICT OF INTEREST
Richard E. Frye has conducted a clinical trial of Kuvan, a commercial form of tetrahydrobioterin, funded by BioMarin Pharmaceuticals Inc. , Novato, CA.

ACKNOWLEDGEMENTS
Edward V. Quadros performs the folate autoantibody analysis in his laboratory.

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