Moduladores del sensor neuronal de calcio DREAMherramientas farmacológicas para el estudio de su interactoma y su aplicación en la enfermedad de Huntington

Abstract

Huntington's disease (HD) is characterized by a combination of motor, psychiatric, and cognitive impairment. Nowdays, it is a neurodegenerative pathology devoided of a treatment that has an impact on its generation and development. Until now, the existing treatments only alleviate the symptoms, without targeting their cause. Therefore, it is crucial the search for new strategies that unravel the molecular basis of this disease and establish the basis for the development of new drugs. In this sense, this Report has been oriented to the study of a novel strategy focused on the search of small molecules that modulate the protein-protein interactions of the neuronal calcium sensor DREAM involved in HD. The aim is to gain knowledge on the processes involved in the generation and progression of this pathology. DREAM, also known as calsenilin or KChIP3, belongs to the superfamily of EFhand calcium binding proteins. The binding of calcium to the DREAM hand-EF domains triggers structural changes that affect their ability to bind to specific DNA sites and to interact with other proteins, modifying their biological functions. At the level of nervous system, the excessive accumulation of calcium has been associated with several neurodegenerative diseases, among them Huntington's disease. In fact, mutated huntingtine has been reported to induce an increase in cellular toxicity, disrupting calcium homeostasis, which results in HD...