Role of KRIT1 in the pathogenesis of Cerebral Cavernous Malformations (CCM): from disease mechanisms toward pharmacological therapies

The Cerebral Cavernous Malformation (CCM) disease accounts for approximately 25 million people worldwide, with a major impact on quality of life and significant socio-economical consequences. Nevertheless, knowledge and risk awareness of this disease is still poor within the society and very low even among medical doctors. To date, there are not direct therapeutic approaches, besides the surgical removal of accessible lesions in patients with recurrent hemorrhage or intractable seizures. To find insights and facilitate breakthroughs into CCM pathogenesis mechanisms and their translational implementation, we established the CCM_Italia multidisciplinary research network (http://www.ccmitalia.unito.it/), which is composed of clinical and research centers located in distinct Italian regions. Through the integrated cooperation of clinicians and researchers with complementary expertise and interests related to distinct aspects of the CCM disease, the CCM_Italia research network is contributing to the characterization of molecular mechanisms underlying CCM disease, providing fundamental insights into the development of novel therapeutic strategies. Here, we show that KRIT1 loss-of-function leads to the upregulation of the redox-sensitive transcription factors, including c-Jun, both in cellular models and human CCM tissues. Furthermore, we demonstrate that c-Jun upregulation can be reversed by either KRIT1 re-expression or ROS scavenging, whereas KRIT1 over-expression prevents forced up-regulation of c-Jun induced by oxidative stimuli. Taken together with the reported role of c-Jun in endothelial dysfunction and vascular permeability triggered by oxidative insults, our findings shed new light into the molecular mechanisms underlying KRIT1 function and CCM pathogenesis, suggesting novel promising therapeutic perspectives.