Defective autophagy is a key feature of cerebral cavernous malformations

Marchi, Saverio; Corricelli, Mariangela; Trapani, Eliana; Bravi, Luca; Pittaro, Alessandra; Monache, Simona Delle; Ferroni, Letizia; Patergnani, Simone; Missiroli, Sonia; Gallelli, Luca; Trabalzini, Lorenza; Rimessi, Alessandro; Giorgi, Carlotta; Zavan, Barbara; Cassoni, Paola; Dejana, Elisabetta; Retta, Saverio Francesco; Pinton, Paolo

doi:10.15252/emmm.201505316

Cited by 113 publications

(156 citation statements)

References 55 publications

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“…On the other hand, there is compelling evidence that antioxidant compounds, such as those indicated above, can induce autophagy, including statins (Andres et al, 2014, Wei et al, 2013, Zhang et al, 2013a), fasudil (Iorio et al, 2010), sulindac derivatives (Chiou et al, 2011, Gurpinar et al, 2013), and vitamin D3 (Hoyer-Hansen et al, 2010, Kim et al, 2012, Lisse and Hewison, 2011, Wu and Sun, 2011). Together with recent findings suggesting that the interplay between defective autophagy and redox imbalance may be integral to the development and progression of CCM lesions by sensitizing endothelial cells to local oxidative stress events (Marchi et al, 2015), these observations point to autophagy as a major redox-sensitive mechanism that justifies the reported effectiveness of the different potential therapeutic compounds described so far (Marchi et al, 2016a, Marchi et al, 2016b). …”

Section: Redox Signaling and Oxidative Stress: The Two Emerging Facessupporting

confidence: 62%

“…Recent findings have also linked defective autophagy to enhanced endothelial cell sensitivity to oxidative stress, which suggests a pathogenetic mechanism that reconciles both the pleiotropic functions of CCM proteins and the distinct therapeutic approaches proposed so far (Marchi et al, 2015, Marchi et al, 2016a, Marchi et al, 2016b). Indeed, it is well established that autophagy inducers limit ROS accumulation and oxidative stress by stimulating the autophagic degradation of ROS-generating mitochondria (Lee et al, 2012, Scherz-Shouval and Elazar, 2011).…”

Section: Redox Signaling and Oxidative Stress: The Two Emerging Facesmentioning

confidence: 94%

“…In this intricate mechanistic scenario, a further level of complexity is added by the discovery that CCM proteins modulate distinct redox-sensitive signaling pathways and mechanisms, including pro-oxidant and antioxidant pathways and autophagy (Gibson et al, 2015, Goitre et al, 2010, Goitre et al, 2014, Guazzi et al, 2012, Marchi et al, 2015), and are implicated in molecular and cellular responses to oxidative stress and inflammatory stimuli (Corr et al, 2012, Goitre et al, 2014). However, besides adding mechanistic complexity, these innovative research findings have also provided a potential integrative explanation for the pleiotropic effects of CCM protein dysfunctions, shedding new light on the mechanisms of CCM pathogenesis and opening new perspectives for disease prevention and treatment ( see Sections below for details ).…”

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

“…In particular, the discovery that defective autophagy is a common feature of loss-of-function of the three known CCM genes and may underlie the major phenotypic hallmarks of CCM disease suggests a potential unifying pathogenic mechanism that reconciles both the broad spectrum of signaling abnormalities and consequent pathologic effects linked to CCM protein dysfunctions, and the distinct therapeutic approaches proposed so far (Marchi et al, 2015, Marchi et al, 2016a, Marchi et al, 2016b). Indeed, most of the reported pleiotropic functions and dysfunctional effects of CCM proteins are directly or indirectly related to autophagy and its tight interconnection with redox homeostasis and signaling (Filomeni et al, 2015, Marchi et al, 2016b, Scherz-Shouval and Elazar, 2011), suggesting that the modulation of autophagy may represent an underlying and unifying mechanism for CCM protein physio-pathological functions.…”

Section: Interplay Between Oxidative Stress and Inflammation In Ccm Dmentioning

confidence: 99%

“…Consistently, autophagy is a converging point of multiple physiological and pathological pathways and may exert pleiotropic effects on several molecular and cellular processes (Choi et al, 2013). Specifically, autophagy plays a pivotal role in various signaling pathways linked to CCM proteins, including pathways involving Sirt1/FoxO1 (Liu et al, 2015, Zhao et al, 2010), JNK/c-Jun (Yogev and Shaulian, 2010), RhoA/ROCK (Mleczak et al, 2013), β-catenin (Lin et al, 2015), TGF-β (Marchi et al, 2015), MEKK3 (Linares et al, 2015), and KLF2/4 (Guixe-Muntet et al, 2016, Liao et al, 2015). Moreover, most phenotypic hallmarks of CCM disease can be linked to autophagic dysfunctions, including enhanced ROS production (Huang et al, 2011, Marchi et al, 2015) and EndMT (Marchi et al, 2015), as well as altered cell adhesion and angiogenic potential (Kim et al, 2013a, Kumar et al, 2013, Tuloup-Minguez et al, 2013), and enhanced endothelial cell sensitivity to oxidant-induced injury (Liu et al, 2015).…”

Section: Interplay Between Oxidative Stress and Inflammation In Ccm Dmentioning

confidence: 99%

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Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

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110

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Graphical abstractTowards a unifying mechanism for CCM disease pathogenesis and treatment.CCM proteins play pleiotropic roles in distinct redox-sensitive pathways by modulating the fine-tuned crosstalk between redox signaling and autophagy. Effective autophagy removes ROS-generating cellular trash, including damaged mitochondria, to rejuvenate cell environment, thus serving a cytoprotective function for the maintenance of endothelial cell monolayer integrity and functionality and blood–brain barrier (BBB) stability even under adverse stress conditions. Loss-of-function of a CCM protein (e.g., KRIT1) causes defective autophagy and altered redox signaling, affecting BBB stability and sensitizing endothelial cells to local oxidative stress and inflammatory events, which may act as key pathogenic determinants of focal formation and progression of CCM lesions. The common capacity to modulate the interplay between autophagy and redox signaling reconciles the distinct pharmacological approaches proposed so far for CCM disease prevention and treatment.

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Section: Redox Signaling and Oxidative Stress: The Two Emerging Facessupporting

confidence: 62%

Section: Redox Signaling and Oxidative Stress: The Two Emerging Facesmentioning

confidence: 94%

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

Section: Interplay Between Oxidative Stress and Inflammation In Ccm Dmentioning

confidence: 99%

Section: Interplay Between Oxidative Stress and Inflammation In Ccm Dmentioning

confidence: 99%

See 3 more Smart Citations

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

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110

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Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease

et al. 2019

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erebral cavernous malformations (CCMs; cavernous angiomas, cavernomas) are low-flow, hemorrhagic vascular lesions of the central nervous system that affect 0.16% to 0.5% of the population. 1 Anatomically, they are composed of abnormal cystic vascular channels lined by a single layer of endothelial cells (ECs) with impaired tight junctions. 2 These vessels are typically arranged in compact masses with no intervening brain parenchyma, so the deriving vascular malformations are angiographically occult. They may undergo acute intracranial hemorrhage (ICH), small subclinical bleeds, or slow diapedesis of red blood cells 3 that produce a characteristic hemosiderin rim on magnetic resonance imaging. 4 In addition to causing stroke from ICH, 5 CCM can also provoke seizures, 6 headaches, and focal neurological deficits (FNDs). 5 About 20% of cases are familial and characterized by the presence of multiple lesions as opposed to sporadic CCM, which has no prevalence within families and typically presents with a single lesion. Radiation-induced cavernous malformation (RICM), a subset of sporadic CCM, can occur in patients previously treated with radiotherapy for brain tumors. Radiation-induced cavernous malformations generally occur after many years, with the time of diagnosis inversely associated with age at radiation treatment. Radiographically and histologically, they are indistinguishable from other sporadic lesions and present similar rates of symptomatic hemorrhage. However, RICM is usually diagnosed at a younger age, and patients are more likely to present with multiple lesions. 7 Cerebral cavernous malformation has a genetic basis. Its mutational landscape has been first investigated in familial forms, where predisposition to develop cavernomas is inherited through an autosomal dominant pattern with incomplete penetrance. Linkage studies allowed associating the occurrence of CCMs with loss-offunction mutations in 1 of 3 genetic loci: CCM1 (KRIT1) at chromosome 7p, 8 CCM2 (MGC4607) at 7q, and CCM3 (PDCD10) at 3q. 9 IMPORTANCE Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. OBSERVATIONS We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies ...

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A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

et al. 2018

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Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

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Defective autophagy is a key feature of cerebral cavernous malformations

Cited by 113 publications

References 55 publications

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

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