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However, the underlying pathophysiology remains poorly understood. In this study, we investigated the mechanisms of dopamine metabolism in post-mortem olfactory bulbs from ten Parkinson\u2019s disease and ten neurologic control subjects. In contrast to the loss of dopaminergic neurons in the midbrain, we observed an increase in tyrosine hydroxylase-positive neurons in the Parkinson\u2019s disease olfactory bulb, suggesting a potential role for dopamine in the hyposmia associated with the condition. Using immunohistochemistry, high-performance liquid chromatography, western blot, and enzyme-linked immunosorbent assays, we demonstrate a reduction in catechol-<jats:italic>O<\/jats:italic>-methyltransferase catabolism of dopamine to homovanillic acid, potentially due to a depletion of the methyl donor substrate <jats:italic>S<\/jats:italic>-adenosyl methionine. We hypothesized that reduction in catechol-<jats:italic>O<\/jats:italic>-methyltransferase activity would result in increased dopamine occupation of the D<jats:sub>2<\/jats:sub> receptor, and consequent inhibition of olfactory processing. Next, we conducted pharmacological interventions to modify dopamine dynamics in hyposmic tau knockout mice, which exhibit altered dopamine metabolism. Our hypothesis was supported by the observation that the D<jats:sub>2<\/jats:sub> receptor antagonist haloperidol temporarily alleviated olfactory deficits in these tau knockout mice. This study implicates a potential role of catechol-<jats:italic>O<\/jats:italic>-methyltransferase-mediated dopamine metabolism in the early olfactory impairments associated with Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1007\/s00401-025-02861-y","type":"journal-article","created":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T07:14:52Z","timestamp":1740813292000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Evidence of COMT dysfunction in the olfactory bulb in Parkinson\u2019s disease"],"prefix":"10.1007","volume":"149","author":[{"given":"Leah C.","family":"Beauchamp","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura J.","family":"Ellett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney M. 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