Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis

Deregulated intracellular Ca2+ and protein homeostasis underlie synaptic dysfunction and are common features in neurodegenerative diseases. DREAM, also known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein of the neuronal calcium sensor superfamily with specific functions through...

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Main Authors: Rocío Naranjo, Paz González, Alejandro Lopez-Hurtado, Xosé M. Dopazo, Britt Mellström, José R. Naranjo
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-12-01
Series:Frontiers in Molecular Neuroscience
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fnmol.2018.00449/full
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author Rocío Naranjo
Rocío Naranjo
Paz González
Paz González
Alejandro Lopez-Hurtado
Alejandro Lopez-Hurtado
Xosé M. Dopazo
Xosé M. Dopazo
Britt Mellström
Britt Mellström
José R. Naranjo
José R. Naranjo
author_facet Rocío Naranjo
Rocío Naranjo
Paz González
Paz González
Alejandro Lopez-Hurtado
Alejandro Lopez-Hurtado
Xosé M. Dopazo
Xosé M. Dopazo
Britt Mellström
Britt Mellström
José R. Naranjo
José R. Naranjo
author_sort Rocío Naranjo
collection DOAJ
description Deregulated intracellular Ca2+ and protein homeostasis underlie synaptic dysfunction and are common features in neurodegenerative diseases. DREAM, also known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein of the neuronal calcium sensor superfamily with specific functions through protein-DNA and protein-protein interactions. Small-molecules able to bind DREAM, like the anti-diabetic drug repaglinide, disrupt some of the interactions with other proteins and modulate DREAM activity on Kv4 channels or on the processing of activating transcription factor 6 (ATF6). Here, we show the interaction of endogenous DREAM and presenilin-2 (PS2) in mouse brain and, using DREAM deficient mice or transgenic mice overexpressing a dominant active DREAM (daDREAM) mutant in the brain, we provide genetic evidence of the role of DREAM in the endoproteolysis of endogenous PS2. We show that repaglinide disrupts the interaction between DREAM and the C-terminal PS2 fragment (Ct-PS2) by coimmunoprecipitation assays. Exposure to sub-micromolar concentrations of repaglinide reduces the levels of Ct-PS2 fragment in N2a neuroblastoma cells. These results suggest that the interaction between DREAM and PS2 may represent a new target for modulation of PS2 processing, which could have therapeutic potential in Alzheimer’s disease (AD) treatment.
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spelling doaj.art-b1f3a54c4c664443b6790d2c4da87c752022-12-21T19:34:30ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-12-011110.3389/fnmol.2018.00449431347Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 EndoproteolysisRocío Naranjo0Rocío Naranjo1Paz González2Paz González3Alejandro Lopez-Hurtado4Alejandro Lopez-Hurtado5Xosé M. Dopazo6Xosé M. Dopazo7Britt Mellström8Britt Mellström9José R. Naranjo10José R. Naranjo11Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainSpanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainSpanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainSpanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainSpanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainSpanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, SpainNational Biotechnology Center (CNB), CSIC, Madrid, SpainDeregulated intracellular Ca2+ and protein homeostasis underlie synaptic dysfunction and are common features in neurodegenerative diseases. DREAM, also known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein of the neuronal calcium sensor superfamily with specific functions through protein-DNA and protein-protein interactions. Small-molecules able to bind DREAM, like the anti-diabetic drug repaglinide, disrupt some of the interactions with other proteins and modulate DREAM activity on Kv4 channels or on the processing of activating transcription factor 6 (ATF6). Here, we show the interaction of endogenous DREAM and presenilin-2 (PS2) in mouse brain and, using DREAM deficient mice or transgenic mice overexpressing a dominant active DREAM (daDREAM) mutant in the brain, we provide genetic evidence of the role of DREAM in the endoproteolysis of endogenous PS2. We show that repaglinide disrupts the interaction between DREAM and the C-terminal PS2 fragment (Ct-PS2) by coimmunoprecipitation assays. Exposure to sub-micromolar concentrations of repaglinide reduces the levels of Ct-PS2 fragment in N2a neuroblastoma cells. These results suggest that the interaction between DREAM and PS2 may represent a new target for modulation of PS2 processing, which could have therapeutic potential in Alzheimer’s disease (AD) treatment.https://www.frontiersin.org/article/10.3389/fnmol.2018.00449/fullpresenilinscalciumDREAMneuronal calcium sensorsrepaglinide
spellingShingle Rocío Naranjo
Rocío Naranjo
Paz González
Paz González
Alejandro Lopez-Hurtado
Alejandro Lopez-Hurtado
Xosé M. Dopazo
Xosé M. Dopazo
Britt Mellström
Britt Mellström
José R. Naranjo
José R. Naranjo
Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
Frontiers in Molecular Neuroscience
presenilins
calcium
DREAM
neuronal calcium sensors
repaglinide
title Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
title_full Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
title_fullStr Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
title_full_unstemmed Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
title_short Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis
title_sort inhibition of the neuronal calcium sensor dream modulates presenilin 2 endoproteolysis
topic presenilins
calcium
DREAM
neuronal calcium sensors
repaglinide
url https://www.frontiersin.org/article/10.3389/fnmol.2018.00449/full
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