Tyrosine hydroxylase (TyrOH) and tryptophan hydroxylase (TrpOH) catalyze the rate-limiting steps in catecholamine (dopamine and norepinephrine) and serotonin biosynthesis, respectively. Alterations in each of these systems have been implicated in mental disorders and, in particular schizophrenia. TyrOH is highly regulated--by protein phosphorylation in the short-term and by transcriptional control in the long-term. Alternative splicing (which occurs exclusively in monkeys and humans) produces multiple TyrOH isoforms having different phosphorylation sites, such that changes in RNA splicing or in relative mRNA/protein turnover rates among isoforms could represent an additional level of regulation. By contrast, despite the close evolutionary and functional similarities between TrpOH and TyrOH, very little is known about the regulation of TrpOH. Moreover, even less is known regarding the status of these enzymes in mental disorders. Postmortem human brain tissue will be analyzed using quantitative blot immunolabeling techniques. TyrOH and TrpOH protein levels, as well as the relative abundances of TyrOH isoforms, will be determined in several brain regions. Depending upon the brain region/monoamine system being studied, DOPA decarboxylase (which catalyzes the second step in catecholamine and serotonin biosynthesis) and dopamine beta-hydroxylase (which converts dopamine to norepinephrine) protein levels will also be determined. The primary study groups will be (a) suicide/sudden death victims having diagnoses of schizophrenia from psychiatric autopsy and (b) age-matched, sudden-death control subjects having no axis 1 mental disorder. Additional toxicological and neuropathological screening criteria will be applied to all cases, and samples will be processed in a blind, matched-pairs design for the neurochemical analyses. Coordination of experimental procedures with ongoing studies of major depressives from the same collection of brains will enable direct comparisons between the disorders. An independent cohort of schizophrenics and age-matched controls (and bipolar affective disorder comparison group) will be used for replicating effects in selected brain regions.
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