title: A brain-specific decrease of the tyrosine hydroxylase protein in sepiapterin reductase-null mice--as a mouse model for Parkinson's disease.
abstract: Sepiapterin reductase (SPR) is an enzyme that acts in the third and final step of tetrahydrobiopterin (BH4) biosynthesis. The human Spr gene locates within the region of 2.5MB mapped to PARK3, an autosomal dominant form of familial Parkinson's diseases. In order to explore the role of SPR in the metabolism of BH4, we produced and analyzed Spr-deficient mice. Most of Spr-null mice survived beyond two weeks. Whereas the BH4 contents in the homozygous mutant mice were greatly decreased than those in wild-type and heterozygous mice, the substantial amounts of BH4 were remained even 17 days after delivery. Spr-null mice exhibited severe monoamine deficiencies and a tremor-like phenotype after weaning. The amount of TH protein in the brain of Spr-null mice was less than 10% of wild-type, while TH protein in the adrenal, phenylalanine hydroxylase protein in the liver, and nNOS in the brain were not altered. These data suggest an essential role of SPR in the biosynthesis of BH4, and that the SPR gene could be a candidate gene for PARK3.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Takazawa
authors.forename: Kengo
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Daigo
authors.initials: D
authors.lastname: Homma
authors.forename: Chiho
authors.initials: C
authors.lastname: Sumi-Ichinose
authors.forename: Takahide
authors.initials: T
authors.lastname: Nomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Setsuko
authors.initials: S
authors.lastname: Katoh
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D014446:Tyrosine 3-Monooxygenase