Chapter 5 - CCM proteins are key players in redox signaling and oxidative stress regulation in Cerebral Cavernous Malformations

Abstract

Cerebral cavernous malformation (CCM) is a genetic disease consisting of closely clustered, abnormally dilated, and leaky capillaries which occur predominantly in the central nervous system. CCM lesions can be single or multiple and may result in severe clinical symptoms, including focal neurological deficits, seizures, and intracerebral hemorrhage. CCM disease has been attributed to mutations in three different genes known as CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10, encoding three structurally unrelated intracellular proteins. These proteins are involved in endothelial cell–cell junction and blood–brain barrier stability maintenance through the regulation of major cellular processes, including endothelial cell–cell and cell–matrix adhesion, actin cytoskeleton dynamics, autophagy, and endothelial-to-mesenchymal transition, suggesting that they act as pleiotropic regulators of cellular homeostasis. Accumulated evidence indicates that the pleiotropic functions of CCM proteins are mainly due to their ability to modulate redox-sensitive pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, thus contributing to the preservation of cellular homeostasis and stress defenses.