Abstract：
Tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine, the initial and rate-limiting step in the synthesis of dopamine, noradrenaline, and adrenaline. Mutations in the human TH gene are associated with hereditary motor disorders. The common C886T mutation identified in the mouse Th gene results in the R278H substitution in the enzyme molecule. We investigated the impact of this mutation on the TH activity in the mouse midbrain. The TH activity in the midbrain of Mus musculus castaneus (CAST) mice homozygous for the 886C allele was higher compared to C57BL/6 and DBA/2 mice homozygous for the 886T allele. Notably, this difference in the enzyme activity was not associated with changes in the Th gene mRNA levels and TH protein content. Analysis of the TH activity in the midbrain in mice from the F2 population obtained by crossbreeding of C57BL/6 and CAST mice revealed that the 886C allele is associated with a high TH activity. Moreover, this allele showed complete dominance over the 886T allele. However, the C886T mutation did not affect the levels of TH protein in the midbrain. These findings demonstrate that the C886T mutation is a major genetic factor determining the activity of TH in the midbrain of common laboratory mouse strains. Moreover, it represents the first common spontaneous mutation in the mouse Th gene whose influence on the enzyme activity has been demonstrated. These results will help to understand the role of TH in the development of adaptive and pathological behavior, elucidate molecular mechanisms regulating the activity of TH, and explore pharmacological agents for modulating its function.
摘要：
酪氨酸羟化酶（TH）催化L-酪氨酸羟化为L-3,4-二羟基苯丙氨酸，多巴胺合成的初始和限速步骤，去甲肾上腺素,和肾上腺素。人TH基因突变与遗传性运动障碍有关。在小鼠Th基因中鉴定的常见C886T突变导致酶分子中的R278H取代。我们研究了这种突变对小鼠中脑TH活性的影响。与886T等位基因纯合的C57BL/6和DBA/2小鼠相比，886C等位基因纯合的栗鼠（CAST）小鼠中脑中的TH活性更高。值得注意的是,酶活性的这种差异与Th基因mRNA水平和TH蛋白含量的变化无关。对通过C57BL/6和CAST小鼠杂交获得的F2群体的小鼠中脑中TH活性的分析表明，886C等位基因与高TH活性有关。此外，该等位基因在886T等位基因上显示出完全的优势。然而,C886T突变不影响中脑TH蛋白水平。这些发现表明，C886T突变是决定常见实验室小鼠品系中脑TH活性的主要遗传因素。此外，它代表了小鼠Th基因中第一个常见的自发突变，其对酶活性的影响已被证明。这些结果将有助于理解TH在适应性和病理行为发展中的作用，阐明调节TH活性的分子机制，并探索调节其功能的药物。
