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: Histological samples of human CCM lesions were obtained from archived paraffin-embedded surgically resected CCM specimens, and p62 levels were evaluated by immunohistochemical studies. The analysis of CCM specimens from 10 cases with confirmed diagnosis of CCM by both neuroradiological and histopathological analyses revealed enhanced staining intensity for p62 in endothelial cells lining CCM lesions (Appendix Table S1). Representative immunohistochemical results for the selected cases are shown in Fig4. While normal brain vascular endothelium deriving from autoptic samples showed negative staining for p62 (Fig4A and B), either moderate (Fig4C and D) or marked (Fig4E and F) “pearl necklace-like” endothelial staining for p62 was observed in the ten CCM cases analyzed (Fig4C–F and Appendix Table S1). Intriguingly, a putative association between marked p62 accumulation and the multiple CCM lesion phenotype was also observed (Appendix Table S1), which deserves further investigation in larger samples for validation. Notably, in one of the eight tissue samples that displayed marked positive p62 staining in CCM lesions, typical normal vessels surrounding the lesion were also present and stained negative for p62, resulting in an internal negative control (Fig4G–I).
Affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.