2. Academic Validation
  3. Defective autophagy is a key feature of cerebral cavernous malformations

Defective autophagy is a key feature of cerebral cavernous malformations

  • EMBO Mol Med. 2015 Nov;7(11):1403-17. doi: 10.15252/emmm.201505316.
Saverio Marchi 1,  Mariangela Corricelli 1,  Eliana Trapani 2,  Luca Bravi 3,  Alessandra Pittaro 4,  Simona Delle Monache 5,  Letizia Ferroni 6,  Simone Patergnani 1,  Sonia Missiroli 1,  Luca Goitre 2,  Lorenza Trabalzini 7,  Alessandro Rimessi 1,  Carlotta Giorgi 1,  Barbara Zavan 6,  Paola Cassoni 4,  Elisabetta Dejana 3,  Saverio Francesco Retta 8,  Paolo Pinton 9
Affiliations

Affiliations

  • 1 Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
  • 2 Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
  • 3 IFOM FIRC Institute of Molecular Oncology, Milano, Italy.
  • 4 Department of Medical Sciences, University of Torino, Torino, Italy.
  • 5 Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy.
  • 6 Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • 7 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
  • 8 Department of Clinical and Biological Sciences, University of Torino, Torino, Italy [email protected] [email protected].
  • 9 Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy [email protected] [email protected].
PMID: 26417067 DOI: 10.15252/emmm.201505316
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.

Keywords

CCM; ROS; autophagy; endothelial‐to‐mesenchymal transition (EndMt); mTOR.

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