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Journal of Neural Transmission

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11.07.2018 | Neurology and Preclinical Neurological Studies - Review Article

Human tyrosine hydroxylase in Parkinson’s disease and in related disorders

verfasst von: Toshiharu Nagatsu, Akira Nakashima, Hiroshi Ichinose, Kazuto Kobayashi

Erschienen in: Journal of Neural Transmission | Ausgabe 4/2019

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Abstract

Parkinson’s disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of l-tyrosine to l-3,4-dihydroxyphenylalanine (l-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline). PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD. However, this decrease in TH is thought to be secondary due to neurodegeneration of DA neurons caused by some as yet unidentified genetic and environmental factors, and thus, TH deficiency may not play a direct role in PD. This manuscript provides an overview of the role of human TH in the pathophysiology of PD, covering the following aspects: (1) structures of the gene and protein of human TH in relation to PD; (2) similarity and dissimilarity between the phenotypes of aging-related sPD and those of young-onset fPD or DOPA-responsive dystonia due to DA deficiency in the striatum with decreased TH activity caused by mutations in either the TH gene or GTP cyclohydrolase I (GCH1) gene; and (3) genetic variants of the TH gene (polymorphisms, rare variants, and mutations) in PD, as discovered recently by advanced genome analysis.

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Titel: Human tyrosine hydroxylase in Parkinson’s disease and in related disorders
verfasst von: Toshiharu Nagatsu
Akira Nakashima
Hiroshi Ichinose
Kazuto Kobayashi
Publikationsdatum: 11.07.2018
Verlag: Springer Vienna
Erschienen in: Journal of Neural Transmission / Ausgabe 4/2019
Print ISSN: 0300-9564
Elektronische ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-018-1903-3

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