RT info:eu-repo/semantics/article
T1 Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment
A1 Lopez-Hurtado, Alejandro
A1 Peraza, Diego A.
A1 Cercos, Pilar
A1 Lagartera, Laura
A1 Gonzalez, Paz
A1 Dopazo, Xose M.
A1 Herranz, Rosario
A1 Gonzalez, Teresa
A1 Martin-Martinez, Mercedes
A1 Mellström, Britt
A1 Naranjo, Jose R.
A1 Valenzuela, Carmen
A1 Gutierrez-Rodriguez, Marta
AB 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.
YR 2019
FD 2019
LK https://uvadoc.uva.es/handle/10324/66029
UL https://uvadoc.uva.es/handle/10324/66029
LA spa
NO Sci Rep . 2019 May 13;9(1):7260. doi: 10.1038/s41598-019-43677-7.
DS UVaDOC
RD 28-nov-2024