The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency
The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency
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DOI：
10.1074/jbc.m900485200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Shimada, Toru
中科院分区：
文献类型：
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作者：
Meng, Yan;Katsuma, Susumu;Shimada, Toru
四氢生物蝶呤(BH4)是芳香酸羟化酶的重要辅因子，控制单胺类神经递质水平。BH4缺乏与许多神经心理障碍有关。BH4生物合成的一个遗传性缺陷是由于缺乏sepiapterin还原酶(SPR)，该酶催化末端的鸟苷三磷酸生物合成BH4。人类SPR基因已定位在与帕金森病发病相关的Park3基因座上。在本研究中，家蚕的体色呈黄色的突变株Lemon(Lem)及其致死等位基因Lemon(1)可作为人类SPR缺乏病的第一个昆虫模型。我们证明SPR基因(BmSpr)的突变是导致LEM和LEM体色不规则的原因(L)。此外，生化分析表明，L(Lem(Lem))幼虫的SPR活性几乎完全减弱，导致幼虫不能取食并在第一次蜕皮后立即死亡。L(Lem(Lem))幼虫口服BH4和多巴胺可有效提高其存活率和摄食能力。我们的数据表明，BmSPR在BH4的产生中起着至关重要的作用，家蚕和lem(L)突变株中的单胺类神经递质将成为解决SPR和BH4缺陷的许多问题的宝贵资源。
Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic acid hydroxylases, which control the levels of monoamine neurotransmitters. BH4 deficiency has been associated with many neuropsychological disorders. An inherited defect in BH4 biosynthesis is caused by the deficiency of sepiapterin reductase (SPR), which catalyzes the biosynthesis of BH4 from guanosine triphosphate at the terminal step. The human SPR gene has been mapped at the PARK3 locus, which is related to the onset of Parkinson disease. In this study, we report that mutant strains, lemon (lem) and its lethal allele lemon lethal (lem(1)) with yellow body coloration, of the silkworm Bombyx mori could be used as the first insect model for human SPR deficiency diseases. We demonstrated that mutations in the SPR gene (BmSpr) were responsible for the irregular body coloration of lem and lem(l). Moreover, biochemical analysis revealed that SPR activity in lem(l) larvae was almost completely diminished, resulting in a lethal phenotype that the larvae cannot feed and that die immediately after the first ecdysis. Oral administration of BH4 and dopamine to lem(l) larvae effectively increased their survival rates and feeding abilities. Our data demonstrate that BmSPR plays a crucial role in the generation of BH4, and monoamine neurotransmitters in silkworms and the lem (lem(l)) mutant strains will be an invaluable resource to address many questions regarding SPR and BH4 deficiencies.