title: A Caenorhabditis elegans model to study dopamine transporter deficiency syndrome.
abstract: 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 in vivo 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 in vivo phenotypic findings demonstrate a functional conservation between human and nematode DAT and validate previous in vitro 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 in vivo tests.
authors: Department of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
authors: Placido
authors: P
authors: Illiano
authors: Department of Biology, Agriculture and Food Science - National Research Council, CNR, Institute of Biosciences and BioResources, IBBR, Via Pietro Castellino 111, 80131, Naples, Italy.
authors: Ambra
authors: A
authors: Lanzo
authors: Department of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
authors: Damiana
authors: D
authors: Leo
authors: Department of Biology, Agriculture and Food Science - National Research Council, CNR, Institute of Biosciences and BioResources, IBBR, Via Pietro Castellino 111, 80131, Naples, Italy.
authors: Maria
authors: M
authors: Paglione
authors: Department of Biology, Agriculture and Food Science - National Research Council, CNR, Institute of Biosciences and BioResources, IBBR, Via Pietro Castellino 111, 80131, Naples, Italy.
authors: Giuseppina
authors: G
authors: Zampi
authors: Institute of Translational Biomedicine, St. Petersburg State University, 199034, St. Petersburg, Russia.|Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow, Russia.
authors: Raul R
authors: RR
authors: Gainetdinov
authors: Department of Biology, Agriculture and Food Science - National Research Council, CNR, Institute of Biosciences and BioResources, IBBR, Via Pietro Castellino 111, 80131, Naples, Italy.
authors: Elia
authors: 0000-0002-8179-6666
authors: E
authors: Di Schiavi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004298:Dopamine
keywords: Caenorhabditis elegans model; DAT1; dopamine; dopamine transporter deficiency syndrome