TY - JOUR
T1 - Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders
T2 - Regulation of dopaminergic neural transmission by tyrosine hydroxylase protein at nerve terminals
AU - Sumi-Ichinose, Chiho
AU - Ichinose, Hiroshi
AU - Ikemoto, Kazuhisa
AU - Nomura, Takahide
AU - Kondo, Kazunao
N1 - Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2010
Y1 - 2010
N2 - 5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa's disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH4 biosynthesis. In order to probe the role of BH4 in vivo, we established BH4-depleted mice by disrupting the 6-pyruvoyltetrahydropterin synthase (PTS) gene (Pts-/-) and rescued them by introducing human PTS cDNA under the control of the human dopamine β-hydroxylase (DBH) promoter (Pts-/--DPS). The Pts-/--DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts-/--DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders.
AB - 5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa's disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH4 biosynthesis. In order to probe the role of BH4 in vivo, we established BH4-depleted mice by disrupting the 6-pyruvoyltetrahydropterin synthase (PTS) gene (Pts-/-) and rescued them by introducing human PTS cDNA under the control of the human dopamine β-hydroxylase (DBH) promoter (Pts-/--DPS). The Pts-/--DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts-/--DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders.
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U2 - 10.1254/jphs.09R28FM
DO - 10.1254/jphs.09R28FM
M3 - Article
C2 - 20716859
AN - SCOPUS:77957953665
VL - 114
SP - 17
EP - 24
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
SN - 1347-8613
IS - 1
ER -