Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice

Mellström, Britt et al.[Background] Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca2+-binding protein that regulates Ca2+ homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory. However, the possible role of DREAM in spine plasticity has not been reported.[Results] Here we show that potentiating DREAM activity, by overexpressing daDREAM, reduced dendritic basal arborization and spine density in CA1 pyramidal neurons and increased spine density in dendrites in dentate gyrus granule cells. These microanatomical changes are accompanied by significant modifications in the expression of specific genes encoding the cytoskeletal proteins Arc, Formin 1 and Gelsolin in daDREAM hippocampus.[Conclusions] Our results strongly suggest that DREAM plays an important role in structural plasticity in the hippocampus.This work was funded by Instituto de Salud Carlos III/CIBERNED (to JRN, BM and JdF), Madrid Community/Neurodegmodels (to JRN), by Ministerio de Economia y Competitividad (grants SAF2010-21784 and SAF2014-53412-R, to JRN) and by Areces Foundation, the EU 6th Framework Program: Network of Excellence NeuroNE (JRN) and the ERA-NET Programs Neuron (JRN), grants from the Medical Research Council (TVPB) and by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, Canadian Institute for Health Research operating grant (MOP-124807), NSERC Discovery Grant (RGPIN 402555) (to MZ). SK had a postdoctoral contract from the Ramón y Cajal Program of the Ministry of Science and Innovation.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HDThis work was funded by the Instituto de Salud Carlos III/CIBERNED (to J.R. Naranjo, B. Mellström, and A. Rábano), FISS-RIC RD12/0042/0019 (to C. Valenzuela), Madrid regional government/Neurodegmodels (to J.R. Naranjo), MINECO grants SAF2010-21784 and SAF2014-53412-R (to J.R. Naranjo), SAF2012-32209 (to M. Gutierrez-Rodriguez), SAF2010-14916 and SAF2013-45800-R (to C. Valenzuela), and a grant from the Swedish Research Council (J.Y. Li

Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington’s disease

Abstract The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca2+ and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington’s disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied. Moreover, it is not known whether DREAM downregulation in HD is unique, or also occurs for other NCS family members. Using the novel object recognition test, we show that chronic administration of the DREAM-binding molecule repaglinide, or induced DREAM haplodeficiency delays onset of cognitive impairment in R6/1 mice, another HD model. The mechanism involves a notable rise in the levels of transcriptionally active ATF6 protein in the hippocampus after repaglinide administration. In addition, we show that reduction in DREAM protein in the hippocampus of HD patients was not accompanied by downregulation of other NCS family members. Our results indicate that DREAM inhibition markedly improves ATF6 processing in the hippocampus and that it might contribute to a delay in memory decline in HD mice. The mechanism of neuroprotection through DREAM silencing in HD does not apply to other NCS family members.This work was funded by the Instituto de Salud Carlos III/CIBERNED (to JRN, BM and AR), the Madrid regional government/Neurodegmodels (to JRN), and SAF2014–53412-R and SAF2017–89554-R (AEI-FEDER, EU) (to JRN)

Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment

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 treatmentThis 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.

Dream neuronal calcium sensor-modulating compounds, and therapeutic uses thereof

[ES] Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos. La presente invención se refiere a un grupo de compuestos con un núcleo estructural derivado de fenilacetamida con la siguiente fórmula (I): que presentan capacidad de modulación del sensor neuronal de calncio DREAM, por lo que la presente invención también se refiere al uso de estos compuestos para el tratamiento o prevención de trastornos o enfermedades donde los niveles de DREAM están por encima o por debajo de los niveles considerados fisiológicamente normales.[EN] The invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having formula (I), which compounds can modulate the DREAM neuronal calcium sensor. Consequently, the invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) y Universidad Autónoma de MadridB1 Patente sin examen previ

Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos

[ES] Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos. La presente invención se refiere a un grupo de compuestos con un núcleo estructural derivado de fenilacetamida con la siguiente fórmula (I): que presentan capacidad de modulación del sensor neuronal de calncio DREAM, por lo que la presente invención también se refiere al uso de estos compuestos para el tratamiento o prevención de trastornos o enfermedades donde los niveles de DREAM están por encima o por debajo de los niveles considerados fisiológicamente normales.[EN] The invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having formula (I), which compounds can modulate the DREAM neuronal calcium sensor. Consequently, the invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) y Universidad Autónoma de MadridA1 Solicitud de patente con informe sobre el estado de la técnic

Dream neuronal calcium sensor-modulating compounds, and therapeutic uses thereof

[ES] Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos. La presente invención se refiere a un grupo de compuestos con un núcleo estructural derivado de fenilacetamida con la siguiente fórmula (I): que presentan capacidad de modulación del sensor neuronal de calncio DREAM, por lo que la presente invención también se refiere al uso de estos compuestos para el tratamiento o prevención de trastornos o enfermedades donde los niveles de DREAM están por encima o por debajo de los niveles considerados fisiológicamente normales.[EN] The invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having formula (I), which compounds can modulate the DREAM neuronal calcium sensor. Consequently, the invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) y Universidad Autónoma de MadridA1 Solicitud de patente con informe sobre el estado de la técnic

Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos

[EN] The invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having formula (I), which compounds can modulate the DREAM neuronal calcium sensor. Consequently, the invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.[ES] Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos. La presente invención se refiere a un grupo de compuestos con un núcleo estructural derivado de fenilacetamida con la siguiente fórmula (I): que presentan capacidad de modulación del sensor neuronal de calncio DREAM, por lo que la presente invención también se refiere al uso de estos compuestos para el tratamiento o prevención de trastornos o enfermedades donde los niveles de DREAM están por encima o por debajo de los niveles considerados fisiológicamente normales.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) y Universidad Autónoma de MadridA1 Solicitud de patente con informe sobre el estado de la técnic

Dream neuronal calcium sensor-modulating compounds, and therapeutic uses thereof

The invention relates to a group of compounds with a structural nucleus derived from phenylacetamide, having formula (I), which compounds can modulate the DREAM neuronal calcium sensor. Consequently, the invention also relates to the use of these compounds for the treatment or prevention of disorders or diseases in which DREAM levels are above or below physiologically normal levels.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universidad Autónoma de MadridA1 Solicitud de patente con informe sobre el estado de la técnic