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During the progression of Parkinson\u2019s disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine \u03b2-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM<jats:sup>+<\/jats:sup>) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation.<\/jats:p>","DOI":"10.1007\/s00702-023-02617-6","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T02:28:57Z","timestamp":1679884137000},"page":"611-625","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson\u2019s disease"],"prefix":"10.1007","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9216-6029","authenticated-orcid":false,"given":"Toshiharu","family":"Nagatsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2383-9816","authenticated-orcid":false,"given":"Akira","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-8536","authenticated-orcid":false,"given":"Hirohisa","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9182-5144","authenticated-orcid":false,"given":"Shosuke","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-9001","authenticated-orcid":false,"given":"Kazumasa","family":"Wakamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-1129","authenticated-orcid":false,"given":"Fabio A.","family":"Zucca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-6653","authenticated-orcid":false,"given":"Luigi","family":"Zecca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-3872","authenticated-orcid":false,"given":"Moussa","family":"Youdim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-8043","authenticated-orcid":false,"given":"Maximilian","family":"Wulf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0520-0373","authenticated-orcid":false,"given":"Peter","family":"Riederer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-3826","authenticated-orcid":false,"given":"Johannes M.","family":"Dijkstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"issue":"1","key":"2617_CR1","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/0006-8993(90)91318-b","volume":"525","author":"ED Abercrombie","year":"1990","unstructured":"Abercrombie ED, Bonatz AE, Zigmond MJ (1990) Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats. 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