Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities
Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities
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DOI：
10.1111/j.1471-4159.2005.03402.x
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发表时间：
2005-11-01
影响因子：
4.7
通讯作者：
Nomura, T
中科院分区：
文献类型：
--
作者：
Sumi-Ichinose, C;Urano, F;Nomura, T
DOPA反应性肌张力障碍（DRD，Segawa病）中可能突变的基因之一是编码GTP环化水解酶I的基因，其是四氢生物蝶呤（BH 4）生物合成的限速酶。基于我们在6-乙酰基四氢蝶呤合酶（PTS）基因破坏（Pts（-/-））小鼠上的发现，我们认为多巴胺能神经末梢中酪氨酸羟化酶（TH）蛋白的量受细胞内BH_4浓度的调节。在本研究中，我们通过转基因导入多巴胺β-羟化酶启动子控制下的人PTS cDNA来拯救Pts（-/-）小鼠，以研究多巴胺能神经元对BH 4-不足的敏感性的区域差异。DPS挽救的（Pts（-/-），DPS）小鼠表现出严重的高苯丙氨酸血症。人PTS在去甲肾上腺素能区域有效表达，但仅在少数多巴胺能神经元中表达。纹状体的生物蝶呤和多巴胺含量以及TH活性与中脑相比恢复较差。纹状体外侧区的TH免疫反应远弱于内侧区或中脑核。我们的结论是，多巴胺能神经末梢投射到纹状体的外侧区域是最敏感的BH-4不足。结果表明，DPS治疗后小鼠的生化和病理变化与人恶性高苯丙氨酸血症和DRD相似。
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) genedisrupted (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.