A Caenorhabditis elegans model to study dopamine transporter deficiency syndrome

Placido Illiano, Ambra Lanzo, Damiana Leo, Maria Paglione, Giuseppina Zampi, Raul R. Gainetdinov, Elia Di Schiavi

Результат исследований: Научные публикации в периодических изданияхстатьярецензирование

8 Цитирования (Scopus)

Аннотация

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.

Язык оригиналаанглийский
Страницы (с-по)207-214
Число страниц8
ЖурналEuropean Journal of Neuroscience
Том45
Номер выпуска1
DOI
СостояниеОпубликовано - 1 янв 2017

Предметные области Scopus

  • Нейробиология (все)

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