title: 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.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan. tnagatsu@fujita-hu.ac.jp.|Department of Brain Functions, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan. tnagatsu@fujita-hu.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nagatsu
authors.affiliation: Department of Anatomy, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nagatsu
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D001708:Biopterins; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin
keywords: Catecholamines; Gene therapy; Parkinson’s disease; Tetrahydrobiopterin; Tyrosine hydroxylase