Fine-tuning DREAM signaling using chemical tools for neurodegenerative disease treatment

Abstract

DREAM (Downstream Regulatory Element Antagonist Modulator), also known as KChIP-3 or calsenilin, is a multifunctional calcium binding protein that controls the expression level and/or the activity of several proteins related to calcium homeostasis, neuronal excitability and neuronal survival. As an auxiliary protein in the plasma membrane, DREAM interacts with, and regulates, the gating of KV4 potassium channels, L- and T-type voltage-dependent calcium channels, NMDA receptors and the transcriptor factor ATF6, which is involved in the unfolding protein response machinary. Considering that altered neuronal calcium homeostasis and the accumulation of poorly folded proteins are common features of many neurodegenerative pathologies, the DREAM modulation could open new avenues for the treatment of neurodegenerative diseases. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD)[1]. However, up to now, only three DREAM binding molecules have been identified. Hence, there is a clear need for the development of chemical tools to modulate and characterize DREAM activity and its interactions. In this communication we will report the identification of novel DREAM modulators by following a multidisciplinary strategy that involves structure-based design, organic chemistry, site-directed mutagenesis and in vitro and in vivo experiments. Our findings open a new avenue in the search of effective treatments of neurodegenerative diseases.