Abstract
The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson’s disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism. DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of TH, AADC, and GCH1 via adeno-associated virus (AAV) vectors.
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Acknowledgements
The author dedicates this article to Dr. Yoshikuni Mizuno, one of his life-long friends. Dr. Mizuno made immense contributions to the pathophysiology of PD, while also being dedicated to clinical work treating many patients (Mizuno 2002) and to the education of medical students and young scientists. The author’s studies were mainly supported by Grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Grants from the Health and Labor of Japan, and several private Research Foundations, which are gratefully acknowledged. The author also would like to dedicate this article to the memory of the late Dr. Keisuke Fujita, Founding President of Fujita Academy and Fujita Health University. The author thanks all of his collaborators, of whom only some are mentioned in References, especially Drs. Hiroshi Ichinose, Kazuto Kobayashi, Mako Mogi, Akira Nakashima, Takahide Nomura, Akira Ota, Toshikuni Sasaoka, Makoto Sawada, and Chiho Sumi Ichinose, as well as Dr. Peter Riederer, for their collaboration for these many years. The author is grateful to Dr. Johannes Dijkstra (Associate Professor, Fujita Health University) for his critical reading of this manuscript. Lastly, I would dedicate this article to Dr. Ikuko (Ishibashi) Nagatsu, who has helped the author throughout the life.
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Dedicated to Prof. Dr. Yoshikuni Mizuno.
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Nagatsu, T. Catecholamines and Parkinson’s disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview. J Neural Transm (2023). https://doi.org/10.1007/s00702-023-02673-y
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DOI: https://doi.org/10.1007/s00702-023-02673-y
Keywords
- Aromatic L-amino acid decarboxylase (AADC)
- Aromatic L-amino acid decarboxylase deficiency
- Dopamine (DA)
- Dopamine β-hydroxylase (DBH)
- DOPA responsive dystonia (DRD)
- Gene therapy
- GTP cyclohydrolase I (GCH1)
- GTP cyclohydrolase I deficiency
- Parkinson’s disease (PD)
- Tetrahydrobiopterin (BH4)
- Tyrosine hydroxylase (TH)
- Tyrosine hydroxylase deficiency