There is a well-established association between alcohol consumption (AC) and folate deficiency (FD). FD is linked to altered mental status and to neuroabnormalities such as subacute combined degeneration of the spinal cord. The latter may be caused by decreased ability to generate methyl groups for methylation reactions essential for synthesis of choline, a major component of the myelin sheath, and biogenic amines. Little is known about folate metabolism in the brain or about the effects of AC or FD on one-carbon metabolism in the brain. The applicant proposes a hypothesis that membrane transport of folates is neurons or glial cells is up-regulated in FD, and this is the reason for the difficulty in depleting folate in the CNS. The applicant also postulated a hypothesis that chronic AC perturbs folate metabolism, which results in decreased methylation of tissue components of the CNS. The applicant will clone the cDNA for the mitochondrial carriers for folate and S-adenosylmethionine (SAM) and determine if FD and/or AC result in up- or down-regulation of expression of these carriers. Since 5,10-methylenetetrahydrofolate (MeTHF) is at a critical juncture in folate metabolism, the applicant hypothesized that its concentration is regulated by conditions, which alter the levels of SAM or 5- methyltetrahydrofolate.
Specific aims i nclude: 1) to investigate the effects of alcohol and/or FD on the uptake of folate by brain tissue using primary cultures of cerebellar granule cells and glial cells. It will also evaluate whether FD and or AC results in up- or down- regulation of the plasma membrane carriers; 2) to examine the effects of AC and/or FD on the metabolism of methyl group and folate in the brain; 3) to examine the effects of AC and/or FD on the methylation of brain phospholipids; to clone and sequence the cDNA for the mitochondrial carriers for folate and SAM and determine if they are regulated by FD and/or AC; and to evaluate the effects of nitrous oxide inactivation of methionine synthase and of administered methionine on the level of MeTHF.
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