Abstract
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.
Highlights
The neuronal calcium sensor DREAM, known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein with specific roles in different subcellular compartments through protein-DNA and/or protein-protein interactions
Real-time quantitative PCR for endogenous PS2 was performed using the assay from Applied Biosystems (Mm00448405_m1)
We have shown that reduction in DREAM protein levels or blockade of DREAM activity, using repaglinide, activates activating transcription factor 6 (ATF6) processing which results in a neuroprotective effect in murine models of Huntington’s disease, delaying the onset and the progression of motor and cognitive decline in these mice (Naranjo et al, 2016; López-Hurtado et al, 2018)
Summary
The neuronal calcium sensor DREAM, known as calsenilin or KChIP-3, is a multifunctional Ca2+ binding protein with specific roles in different subcellular compartments through protein-DNA and/or protein-protein interactions. In the nucleus DREAM binds to DRE sites in the DNA and represses transcription of target genes (Carrión et al, 1999). DREAM interacts with other nucleoproteins, like CREB, CtBP1, nuclear receptors or TTF-1 and modifies their transcriptional function (Ledo et al, 2002; Rivas et al, 2004; Scsucova et al, 2005; Zaidi et al, 2006). The DREAM interactome comprises a heterogeneous set of proteins encompassing ion channels, membrane receptors, GRK kinases and presenilins (PSs), among others (reviewed in Rivas et al, 2011; Burgoyne and Haynes, 2012). Binding to Ca2+ induces conformational changes in DREAM that prevents DREAM binding to DRE sites in the DNA (Carrión et al, 1999) and distinctly modifies the interaction
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