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首页> 外文期刊>The European Journal of Neuroscience >A Caenorhabditis elegans model to study dopamine transporter deficiency syndrome
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A Caenorhabditis elegans model to study dopamine transporter deficiency syndrome

机译：研究多巴胺转运综合征的Caenorhabditis elegans模型

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Dopamine transporter deficiency syndrome (DTDS) is a novel autosomal recessive disorder caused by mutations in the dopamine transporter (DAT), which leads to the partial or total loss of function of the protein. DTDS is a pharmacoresistant syndrome and very little is known about its neurobiology, in part due to the lack of relevant animal models. The objective of this study was to establish the first animal model for DTDS with strong construct validity, using Caenorhabditis elegans, and to investigate the invivo role played by DTDS-related mutations found in human DAT (hDAT). We took advantage of a C.elegans knockout for the hDAT orthologue, cedat-1, to obtain genetically humanized animals bearing hDAT, in the wild type and in two mutated forms (399delG and 941C>T), in a null background. In C.elegans transgenic animals expressing the human wild-type form, we observed a rescue of the knockout phenotype, as assessed using two well-established paradigms, known to be regulated by the endogenous uptake of dopamine or 6-hydroxydopamine (6-OHDA) by DAT. The less severe mutation (941C>T) was able to partially rescue only one of the knockout phenotypes, whereas the 399delG mutation impaired DAT function in both phenotypic paradigms. Our invivo phenotypic findings demonstrate a functional conservation between human and nematode DAT and validate previous invitro indications of the loss of function of hDAT in carriers of DTDS-related mutations. Taken together, these observations establish C.elegans as a novel animal model for fast and inexpensive screening of hDAT mutations in functional and invivo tests.
机译：多巴胺转运蛋白缺乏综合征（DTD）是由多巴胺转运蛋白（DAT）中的突变引起的新型常血糖隐性疾病，这导致蛋白质的部分或全部损失。 DTD是一种药质渗透综合征，并且关于其神经生物学的众所周知，部分是由于缺乏相关的动物模型。本研究的目的是使用Caenorhabditis elegans建立具有强大构建有效性的DTD的第一类动物模型，并研究人类数据（HDAT）中发现的DTDS相关突变发挥的Invivo作用。我们利用C.Elegans淘汰赛的HDAT正轨，即核心化动物，以野生型和两种突变形式（399DelG和941C> T）获得含HDAT的遗传拟人源化动物。在表达人类野生型形式的C.Elegans转基因动物中，我们观察到敲除表型的救援，如使用两种成熟的范例评估，已知由多巴胺或6-羟基多巴胺的内源摄取（6-OHDA ）通过DAT。较小的突变（941c> t）能够仅部分拯救仅敲除表型，而399delg突变在两种表型范式中的DAT功能损害。我们的Invivo表型调查结果表明了人和线虫之间的功能守恒，并验证了与DTDS相关突变载体中HDAT功能丧失的先前邀请症。总之，这些观察结果建立了C.Elegans作为功能性和Invivo测试中的HDAT突变的快速和廉价筛选的新型动物模型。

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