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Journal of Neural Transmission

, Volume 123, Issue 11, pp 1255–1278 | Cite as

Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): historical overview and future prospects

  • Toshiharu NagatsuEmail author
  • Ikuko Nagatsu
Translational Neurosciences - Review Article

Abstract

Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson’s disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic l-amino acid decarboxylase (AADC); dopamine β-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD. We purified all human CA-synthesizing enzymes, produced their antibodies for immunohistochemistry and immunoassay, and cloned all human genes, especially the human TH gene and the human gene for GCH1, which synthesizes BH4 as a cofactor of TH. This review discusses the historical overview of TH, BH4-, and other CA-related enzymes and their genes in relation to the pathophysiology of PD, the development of drugs, such as l-DOPA, and future prospects for drug and gene therapy for PD, especially the potential of induced pluripotent stem (iPS) cells.

Keywords

Tyrosine hydroxylase Tetrahydrobiopterin Catecholamines Parkinson’s disease Gene therapy 

Notes

Acknowledgments

We thank all of our former colleagues and international collaborators described in References, especially Drs. Makoto Sawada, Kazuto Kobayashi, Hiroshi Ichinose, Chiho Sumi-Ichinose, Toshikuni Sasaoka, Makio Mogi, Takahide Nomura, Akira Ota, and Akira Nakashima, as well as Dr. Peter Riederer for their collaboration over these many years. The main parts of the work were supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Ministry of Health, Labor, and Welfare of Japan. In the light of their encouragement to us for over 50 years to promote our research in the field of catecholamines, we would like to dedicate this manuscript to the memory of the late Dr. Sidney Udenfriend of the National Institutes of Health, Roche Institute of Molecular Biology and Drew University, the late Dr. Julius Axelrod of the National Institutes of Health, and the late Dr. Keisuke Fujita of Fujita Health University.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. 1.Department of Pharmacology, School of MedicineFujita Health UniversityToyoakeJapan
  2. 2.Department of Anatomy, School of MedicineFujita Health UniversityToyoakeJapan
  3. 3.Department of Brain Functions, Research Institute of Environmental MedicineNagoya UniversityNagoyaJapan

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