MELATONIN SYNTHESIS IN THE WILSONS DISEASE ANIMAL MODEL

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DESCRIPTION (Adapted from applicant's abstract): Circadian rhythms and environmental lighting regulate nightly synthesis of melatonin, the pineal hormone implicated in various aspects of human physiology including sleep-wakefulness cycle and manic-depressive illnesses. To understand the cellular mechanisms underlying the dynamic regulation of melatonin production, a substractive hybridization technique was employed to search for messages differentially expressed during day and night in the rat pineal gland. Using this technique, an alternatively spliced form of the Wilson's disease gene (PIneal Night-specific ATPase = PINA) was found to be prominently expressed in night pineal gland. Tissue distribution and temporal expression pattern of PINA are identical to that of serotonin N-acetyltransferase (NAT), the rate limiting enzyme in melatonin synthesis, suggesting a role of PINA in melatonin production. Long Evans Cinnamon (LEC) rats are animal models of the Wilson's disease in which PINA is mutated. Preliminary studies revealed that the activity of serotonin NAT is decreased in these rats while that of hydroxyindole-O-methyltransferase (HIOMT), the second and the last enzyme in melatonin synthesis, is unaltered. This proposal is designed to further analyze the functional consequence of PINA mutation in LEC pineal and to elucidate molecular mechanism underlying this defect.