Defective autophagy is a key feature of cerebral cavernous malformations.
Bottom Line: 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.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.
Affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.Show MeSH
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Mentions: p62/SQSTM1 acts as a receptor for ubiquitinated cargoes and delivers them to the autophagosome, and p62 itself is incorporated into the autophagosome and subsequently degraded by autophagy (Komatsu et al, 2007). The autophagy protein microtubule-associated protein 1 light chain 3 (LC3) is present in the cytosol in the LC3-I form, until it is modified to a cleaved and lipidated membrane-bound form (LC3-II), which is localized to autophagosomes. Thus, in addition to p62 accumulation, another typical trait of autophagy inhibition consists of increased amounts of the cytosolic non-lipidated form of LC3 (LC3-I) and of total LC3 (Mizushima et al, 2010; Wang et al, 2012). As shown in Fig1A, KRIT1 deficiency was associated with defective autophagy, displaying increased levels of p62 and total LC3.
Affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.