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When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters

The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the...

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Autores principales: Sucic, Sonja, Kasture, Ameya, Mazhar Asjad, H. M., Kern, Carina, El-Kasaby, Ali, Freissmuth, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386142/
https://www.ncbi.nlm.nih.gov/pubmed/28405636
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author Sucic, Sonja
Kasture, Ameya
Mazhar Asjad, H. M.
Kern, Carina
El-Kasaby, Ali
Freissmuth, Michael
author_facet Sucic, Sonja
Kasture, Ameya
Mazhar Asjad, H. M.
Kern, Carina
El-Kasaby, Ali
Freissmuth, Michael
author_sort Sucic, Sonja
collection PubMed
description The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.
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spelling pubmed-53861422017-04-10 When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters Sucic, Sonja Kasture, Ameya Mazhar Asjad, H. M. Kern, Carina El-Kasaby, Ali Freissmuth, Michael J Neurol Neuromedicine Article The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation. 2016-12-30 /pmc/articles/PMC5386142/ /pubmed/28405636 Text en http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Sucic, Sonja
Kasture, Ameya
Mazhar Asjad, H. M.
Kern, Carina
El-Kasaby, Ali
Freissmuth, Michael
When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title_full When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title_fullStr When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title_full_unstemmed When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title_short When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters
title_sort when transporters fail to be transported: how to rescue folding-deficient slc6 transporters
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386142/
https://www.ncbi.nlm.nih.gov/pubmed/28405636
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