2026-04-27T01:38:04Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/660292024-12-16T11:15:14Zcom_10324_1134com_10324_931com_10324_894col_10324_1213

Lopez-Hurtado, Alejandro Peraza Pérez, Diego Alberto Cercos, Pilar Lagartera, Laura Gonzalez, Paz Dopazo, Xose M. Herranz, Rosario Gonzalez, Teresa Martin-Martinez, Mercedes Mellström, Britt Naranjo, Jose R. Valenzuela, Carmen Gutierrez-Rodriguez, Marta 2024-02-08T17:01:22Z 2024-02-08T17:01:22Z 2019 Sci Rep . 2019 May 13;9(1):7260. doi: 10.1038/s41598-019-43677-7. https://uvadoc.uva.es/handle/10324/66029 10.1038/s41598-019-43677-7 1 Scientific Reports 9 2045-2322 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. application/pdf spa info:eu-repo/semantics/openAccess Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion SI