Abstract
Dopamine (DA) is a precursor of neuromelanin (NM) synthesized in the substantia nigra of the brain. NM is known to contain considerable levels of Fe and Cu. However, how Fe and Cu ions affect DA oxidation to DA-eumelanin (DA-EM) and modify its structure is poorly understood. EMs were prepared from 500 µM DA, dopaminechrome (DAC), or 5,6-dihydroxyindole (DHI). Autoxidation was carried out in the absence or presence of 50 µM Fe(II) or Cu(II) at pH 7.4 and 37 ℃. EMs were characterized by Soluene-350 solubilization analyzing absorbances at 500 nm (A500) and 650 nm (A650) and alkaline hydrogen peroxide oxidation (AHPO) yielding various pyrrole carboxylic acids. Pyrrole-2,3,4,5-tetracarboxylic acid (PTeCA) served as a molecular marker of cross-linked DHI units. Importantly, Fe and Cu accelerated DA oxidation to DA-EM and DHI oxidation to DHI-EM several-fold, whereas these metals only weakly affected the production of DAC-EM. The A500 values indicated that DA-EM contains considerable portions of uncyclized DA units. Analysis of the A650/A500 ratios suggests that Fe and Cu caused some degradation of DHI units of DA-EM during 72-h incubation. Results with AHPO were consistent with the A500 values and additionally revealed that (1) DA-EM is less cross-linked than DAC-EM and DHI-EM and (2) Fe and Cu promote cross-linking of DHI units. In conclusion, Fe and Cu not only accelerate the oxidation of DA to DA-EM but also promote cross-linking and degradation of DHI units. These results help to understand how Fe and Cu in the brain affect the production and properties of NM.
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Data availability statement
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Abbreviations
- A500:
-
Absorbance at 500 nm
- A650:
-
Absorbance at 650 nm
- AHPO:
-
Alkaline hydrogen peroxide oxidation
- Cys:
-
l-Cysteine
- DHI:
-
5,6-Dihydroxyindole
- DHICA:
-
5,6-Dihydroxyindole-2-carboxylic acid
- DOPA:
-
l-3,4-dihydroxyphenylalanine
- DA:
-
Dopamine
- DAC:
-
Dopamine-chrome
- DAQ:
-
Dopamine-quinone
- EM:
-
Eumelanin
- isoPTCA:
-
Pyrrole-2,3,4-tricarboxylic acid
- LC:
-
Locus coeruleus
- NM:
-
Neuromelanin
- NE:
-
Norephinephrine
- PDCA:
-
Pyrrole-2,3-dicarboxylic acid
- PTCA:
-
Pyrrole-2,3,5-tricarboxylic acid
- PTeCA:
-
Pyrrole-2,3,4,5-tetracarboxylic acid
- SN:
-
Substantia nigra
- ROS:
-
Reactive oxygen species
- PD:
-
Parkinson's disease
- Cys-DA:
-
Cysteinyldopamin
- PDA:
-
Polydopamine
- GSH:
-
Glutathione
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Acknowledgements
This original article was presented at the Mini-Symposium “The Puzzle of how Neuromelanin and Other Factors affect Parkinson’s Disease”, held on July 15, 2022 online. The authors acknowledge helpful discussions and comments by Drs. Toshiharu Nagatsu (Fujita Health University, Japan), Peter Riederer (University of Würzburg, Germany), Luigi Zecca (Institute of Biomedical Technologies-CNR, Italy), Moussa Youdim (Technion-Rappaport Family Faculty of Medicine, Israel), Xiqun Chen (Harvard University, USA), and Hans Dijkstra (Fujita Health University, Japan).
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Conceptualization: SI, KW; methodology: SI; data analysis: SI; writing—original draft preparation: SI, AN, TS, KW; writing—review and editing: SI, AN, TS, KW. All authors have read and agreed to the published version of the manuscript.
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Ito, S., Napolitano, A., Sarna, T. et al. Iron and copper ions accelerate and modify dopamine oxidation to eumelanin: implications for neuromelanin genesis. J Neural Transm 130, 29–42 (2023). https://doi.org/10.1007/s00702-022-02574-6
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DOI: https://doi.org/10.1007/s00702-022-02574-6