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      Defective autophagy gets to the brain

      ,

      Oncotarget

      Impact Journals LLC

      cerebral cavernous malformations, endothelial-to-mesenchymal transition, KRIT1, LC3, MTOR, p62

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          Abstract

          Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates in the lysosomal degradation of useless or potentially dangerous intracellular entities, be them endogenous (like damaged organelles) or exogenous (like invading bacteria). Autophagy not only contributes to the maintenance of cellular homeostasis in physiological conditions, but also plays an essential role in adaptation to stress. In line with this notion, defective autophagy has been etiologically implicated in a wide range of human pathologies, including cancer, inflammatory disorders and neurodegenerative conditions. Recent data demonstrate that autophagic defects also contribute to the development of genetic neurovascular conditions commonly known as cerebral cavernous malformations (CCMs). CCMs (OMIM 116860, also known as cavernous angiomas or cavernomas) are neurovascular malformations that consist in clustered, aberrantly dilated and leaky capillaries lined up by a scarce endothelium and lacking normal structural components. CCMs can be inherited as a dominant autosomal disease with partial penetrance and variable expressivity or develop sporadically. Approximately 85-95% of familial CCM cases have been attributed to loss-of-function mutations in either of three genes: KRIT1, ankyrin repeat containing (KRIT1), cerebral cavernous malformation 2 (CCM2) and programmed cell death 10 (PDCD10). Mutations in unidentified genes or other hitherto unknown causes have been invoked to account for the remaining 5-15% cases of familial CCMs. In approximately 1/3 of cases, CCMs manifest clinically with moderate-to-severe symptoms including headaches, neurological deficits, seizures, strokes, and intracerebral hemorrhages. Of note, no treatment options other than the surgical resection of accessible lesions are currently available for subjects with clinically manifest CCMs [1]. Paolo Pinton and colleagues (from the University of Ferrara, Italy) have recently reported that various cell types subjected to the genetic inhibition of KRIT1 (by gene knockout or RNA interference) exhibit increased levels of two proteins that are normally processed (and degraded) by autophagy, i.e., sequestosome 1 (SQSTM1, best known as p62) and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B, best known as LC3B) [2]. Such a defect was accompanied by the hyperactivation of mechanistic target of rapamycin (MTOR), a kinase with prominent autophagy-suppressing functions, and could be reversed (at least in part) by the reconstitution of KRIT1 activity as well as by the administration of two distinct pharmacological MTOR inhibitors [3, 4], namely, rapamycin and Torin 1. Similar data were obtained in Pdcd10 −/− cells. Moreover, the inability of KRIT1- deficient cells to properly process p62 and LC3 appeared to stem from defects in the late (rather than in the early) steps of autophagy, i.e., in the fusion of autophagosomes with lysosomes or in the lysosomal degradation of the autophagic cargo [5]. KRIT1-deficient cells exhibited molecular features of the so-called “endothelial-to-mesenchymal transition”, a phenotypic and biochemical shift that has previously been associated with CCMs [6]. Such molecular markers could be reversed by treating KRIT1-deficient cells with pharmacological MTOR inhibitors. Moreover, the small-interfering RNA (siRNA)-mediated depletion of an essential component of the autophagic machinery, i.e., autophagy-related 7 (ATG7), in KRIT1-proficient cells was associated with the appearance of both molecular and behavioral biomarkers of the mesenchymal state. Finally, in a mouse model of CCMs as well as in autoptic samples from CCM patients, endothelial cells from pathognomonic lesions (but not from the adjacent, normal brain) exhibited variable degrees of p62 accumulation [5]. Taken together, these data implicate defective autophagy in the pathogenesis of CCMs, and raise several important questions. First, what are the molecular mechanisms linking KRIT1 loss-of-function mutations to autophagic defects? Second, do mutations in CCM2 and PDCD10 cause similar defects or do they operate at distinct levels of the autophagic cascade? Third, is the accumulation of p62 that drives CCM pathogenesis or does this reflect a generalized impairment in endothelial cell homeostasis? Fourth, and presumably most important, would the administration of MTOR inhibitors (some of which are currently approved by regulatory agencies as immunosuppressants) [7] benefit to CCM patients? Further experiments are required to solve these incognita.

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          Most cited references 7

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          Autophagy in malignant transformation and cancer progression.

          Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
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            EndMT contributes to the onset and progression of cerebral cavernous malformations.

            Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.
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              • Record: found
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              Organelle-Specific Initiation of Autophagy.

              Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates ("offer") and the cellular need of autophagic products or functions for adaptation ("demand"). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions.
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                Author and article information

                Affiliations
                Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
                Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
                Author notes
                Correspondence to: Lorenzo Galluzzi, deadoc@ 123456vodafone.it
                Correspondence to: Guido Kroemer, kroemer@ 123456orange.fr
                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                24 November 2015
                13 November 2015
                : 6
                : 37
                : 39396-39397
                4741833
                26575951
                Copyright: © 2015 Galluzzi and Kroemer

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Editorial: Autophagy and Cell Death

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