Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6506
Title: Defective autophagy is a key feature of cerebral cavernous malformations
Authors: Marchi, Saverio
Corricelli, Mariangela
Trapani, Eliana
Bravi, Luca
Pittaro, Alessandra
Delle Monache, Simona
Ferroni, Letizia
Patergnani, Simone
Missiroli, Sonia
Goitre, Luca
Trabalzini, Lorenza 
Rimessi, Alessandro
Giorgi, Carlotta
Zavan, Barbara
Cassoni, Paola
Dejana, Elisabetta
Retta, Saverio Francesco
Pinton, Paolo
Keywords: Autophagy; CCM; Endothelial-to-mesenchymal transition (EndMt); mTOR; ROS; Molecular Medicine
Issue Date: 2015
Project: None 
Journal: EMBO MOLECULAR MEDICINE
Abstract: 
Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.
Description: 
205553
URI: http://hdl.handle.net/20.500.12779/6506
ISSN: 1757-4676
DOI: 10.15252/emmm.201505316
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