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Defective autophagy is a key feature of cerebral cavernous malformations.

Marchi S, Corricelli M, Trapani E, Bravi L, Pittaro A, Delle Monache S, Ferroni L, Patergnani S, Missiroli S, Goitre L, Trabalzini L, Rimessi A, Giorgi C, Zavan B, Cassoni P, Dejana E, Retta SF, Pinton P - EMBO Mol Med (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.

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Accumulation of p62 in endothelial cells lining human CCM lesionsp62 immunohistochemical (IHC) staining in human brain tissue.A, B Normal vascular endothelium of autoptic brain parenchyma samples is lacking the typical autophagic p62 granules as shown by the negative staining for p62. Scale bars: (A) 200 μm; (B) 100 μm.C–F Two different representative samples of CCM lesions with a thin, single layer brain endothelium displaying either moderate (C, D) or marked (E, F) positive perinuclear “pearl necklace-like” immunostaining for p62 granules. (C, D), case n° 4 (p62++), and (E, F), case n° 8 (p62+++) are representative of CCM cases listed in Appendix Table S1. Scale bars: (C, E) 200 μm; (D, F) 100 μm. Arrows indicate endothelial p62 positive staining.G–I Hematoxylin and eosin (H&E) staining (G) and p62 immunohistochemical analysis (H, I) of a CCM surgical sample (case n° 6 in Appendix Table S1) containing normal vessels in the peri-lesional area, which served as an internal control. Notice marked p62-positive staining in endothelial cells lining a CCM lesion (H, arrows) and p62-negative staining in endothelial cells lining a normal peri-lesional vessel (I, arrows). Scale bars: (G) 300 μm; (H, I) 100 μm. Background staining in brain parenchyma surrounding CCM lesions may be attributed to either cell debris or p62 immunoreactivity in neuronal and glial cells.
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fig04: Accumulation of p62 in endothelial cells lining human CCM lesionsp62 immunohistochemical (IHC) staining in human brain tissue.A, B Normal vascular endothelium of autoptic brain parenchyma samples is lacking the typical autophagic p62 granules as shown by the negative staining for p62. Scale bars: (A) 200 μm; (B) 100 μm.C–F Two different representative samples of CCM lesions with a thin, single layer brain endothelium displaying either moderate (C, D) or marked (E, F) positive perinuclear “pearl necklace-like” immunostaining for p62 granules. (C, D), case n° 4 (p62++), and (E, F), case n° 8 (p62+++) are representative of CCM cases listed in Appendix Table S1. Scale bars: (C, E) 200 μm; (D, F) 100 μm. Arrows indicate endothelial p62 positive staining.G–I Hematoxylin and eosin (H&E) staining (G) and p62 immunohistochemical analysis (H, I) of a CCM surgical sample (case n° 6 in Appendix Table S1) containing normal vessels in the peri-lesional area, which served as an internal control. Notice marked p62-positive staining in endothelial cells lining a CCM lesion (H, arrows) and p62-negative staining in endothelial cells lining a normal peri-lesional vessel (I, arrows). Scale bars: (G) 300 μm; (H, I) 100 μm. Background staining in brain parenchyma surrounding CCM lesions may be attributed to either cell debris or p62 immunoreactivity in neuronal and glial cells.

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).


Defective autophagy is a key feature of cerebral cavernous malformations.

Marchi S, Corricelli M, Trapani E, Bravi L, Pittaro A, Delle Monache S, Ferroni L, Patergnani S, Missiroli S, Goitre L, Trabalzini L, Rimessi A, Giorgi C, Zavan B, Cassoni P, Dejana E, Retta SF, Pinton P - EMBO Mol Med (2015)

Accumulation of p62 in endothelial cells lining human CCM lesionsp62 immunohistochemical (IHC) staining in human brain tissue.A, B Normal vascular endothelium of autoptic brain parenchyma samples is lacking the typical autophagic p62 granules as shown by the negative staining for p62. Scale bars: (A) 200 μm; (B) 100 μm.C–F Two different representative samples of CCM lesions with a thin, single layer brain endothelium displaying either moderate (C, D) or marked (E, F) positive perinuclear “pearl necklace-like” immunostaining for p62 granules. (C, D), case n° 4 (p62++), and (E, F), case n° 8 (p62+++) are representative of CCM cases listed in Appendix Table S1. Scale bars: (C, E) 200 μm; (D, F) 100 μm. Arrows indicate endothelial p62 positive staining.G–I Hematoxylin and eosin (H&E) staining (G) and p62 immunohistochemical analysis (H, I) of a CCM surgical sample (case n° 6 in Appendix Table S1) containing normal vessels in the peri-lesional area, which served as an internal control. Notice marked p62-positive staining in endothelial cells lining a CCM lesion (H, arrows) and p62-negative staining in endothelial cells lining a normal peri-lesional vessel (I, arrows). Scale bars: (G) 300 μm; (H, I) 100 μm. Background staining in brain parenchyma surrounding CCM lesions may be attributed to either cell debris or p62 immunoreactivity in neuronal and glial cells.
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fig04: Accumulation of p62 in endothelial cells lining human CCM lesionsp62 immunohistochemical (IHC) staining in human brain tissue.A, B Normal vascular endothelium of autoptic brain parenchyma samples is lacking the typical autophagic p62 granules as shown by the negative staining for p62. Scale bars: (A) 200 μm; (B) 100 μm.C–F Two different representative samples of CCM lesions with a thin, single layer brain endothelium displaying either moderate (C, D) or marked (E, F) positive perinuclear “pearl necklace-like” immunostaining for p62 granules. (C, D), case n° 4 (p62++), and (E, F), case n° 8 (p62+++) are representative of CCM cases listed in Appendix Table S1. Scale bars: (C, E) 200 μm; (D, F) 100 μm. Arrows indicate endothelial p62 positive staining.G–I Hematoxylin and eosin (H&E) staining (G) and p62 immunohistochemical analysis (H, I) of a CCM surgical sample (case n° 6 in Appendix Table S1) containing normal vessels in the peri-lesional area, which served as an internal control. Notice marked p62-positive staining in endothelial cells lining a CCM lesion (H, arrows) and p62-negative staining in endothelial cells lining a normal peri-lesional vessel (I, arrows). Scale bars: (G) 300 μm; (H, I) 100 μm. Background staining in brain parenchyma surrounding CCM lesions may be attributed to either cell debris or p62 immunoreactivity in neuronal and glial cells.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.

Show MeSH
Related in: MedlinePlus