Mañana, JUEVES, 24 DE ABRIL, el sistema se apagará debido a tareas habituales de mantenimiento a partir de las 9 de la mañana. Lamentamos las molestias.
Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment
Entity
UAM. Departamento de BioquímicaPublisher
Nature ResearchDate
2019-05-13Citation
10.1038/s41598-019-43677-7
Sci Rep 9 (2019): 7260
ISSN
2045-2322DOI
10.1038/s41598-019-43677-7Funded by
This work was funded by the Spanish Ministery of Economy, Industry and Competitivity (AEI-FEDER, EU grants): BFU2015-67284-R (to M.G.R., R.H.), SAF2017-89554-R (to J.R.N.), SAF2016-75021-R (to C.V.) and SAF2015-66275-C2-2-R (to M.M.M.); the Instituto de Salud Carlos III CIBERNED and CIBERCV programs (to J.R.N. and to C.V., respectively) and the Madrid regional government/Neurodegmodels (to J.R.N.); CSIC grant PIE201880E109 (to M.G.R., R.H. and M.M.M.) and PIE201820E104 (to C.V.)Project
Gobierno de España. BFU2015-67284-R; Gobierno de España. SAF2017-89554-R; Gobierno de España. SAF2016-75021-R; Gobierno de España. SAF2015-66275-C2-2-REditor's Version
https://doi.org/10.1038/s41598-019-43677-7Subjects
Huntington’s disease (HD); calcium sensor; treatment; Biología y Biomedicina / BiologíaRights
© The Author(s) 2019Abstract
DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington’s disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on KV4.3 channel gating and blocked the ATF6/DREAM interaction. Our results validate DREAM as a valuable target and propose more effective molecules for HD treatment
Files in this item
Google Scholar:López-Hurtado, Alejandro
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Peraza, Diego A.
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Cercos, Pilar
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Lagartera, Laura
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González, Paz
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Dopazo, Xose M.
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Herranz, Rosario
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González Gallego, Teresa
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Martin-Martínez, Mercedes
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Mellström, Britt
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Naranjo, José R.
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Valenzuela, Carmen
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Gutierrez-Rodríguez, Marta
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