TY - JOUR
T1 - A brain-specific decrease of the tyrosine hydroxylase protein in sepiapterin reductase-null mice-as a mouse model for Parkinson's disease
AU - Takazawa, Chisato
AU - Fujimoto, Kengo
AU - Homma, Daigo
AU - Sumi-Ichinose, Chiho
AU - Nomura, Takahide
AU - Ichinose, Hiroshi
AU - Katoh, Setsuko
N1 - Funding Information:
This work was supported by the Research Grant (18A-2) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare of Japan, Grants (No. 15791067 and No. 17791329) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Grants-in-aid (No. 17024017) for Scientific Research on Priority Areas-Molecular Brain Science from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the Miyata Foundation of Meikai University.
PY - 2008/3/21
Y1 - 2008/3/21
N2 - 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 2.5 MB 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.
AB - 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 2.5 MB 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.
KW - Knock-out mouse
KW - NO synthase
KW - Phenylalanine hydroxylase
KW - Sepiapterin reductase
KW - Tetrahydrobiopterin
KW - Tyrosine hydroxylase
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U2 - 10.1016/j.bbrc.2008.01.028
DO - 10.1016/j.bbrc.2008.01.028
M3 - Article
C2 - 18201550
AN - SCOPUS:38649121457
SN - 0006-291X
VL - 367
SP - 787
EP - 792
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -