Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities.
One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6-pyruvoyltetrahydropterin synthase (PTS) gene-disrupted (Pts(-/-)) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts(-/-) mice by transgenic introduction of human PTS cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.
Sumi-Ichinose
Chiho
C
Department of Pharmacology, School of Medicine, Fujita Health University, Tokoake, Aichi, Japan. csichino@fujita-hu.ac.jp
Urano
Fumi
F
Shimomura
Atsushi
A
Sato
Takashi
T
Ikemoto
Kazuhisa
K
Shiraishi
Hiroaki
H
Senda
Takao
T
Ichinose
Hiroshi
H
Nomura
Takahide
T
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006130:Growth Disorders / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D008636:Mesencephalon / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000502:physiology; D009830:Olfactory Bulb / Q000502:physiology; D010661:Phenylketonurias / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014886:Weaning
D001708:Biopterins; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; C003402:sapropterin; D004298:Dopamine; D009638:Norepinephrine