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      Retention of Mitochondria in Mature Human Red Blood Cells as the Result of Autophagy Impairment in Rett Syndrome

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          Abstract

          Rett Syndrome (RTT), which affects approximately 1:10.000 live births, is a X-linked pervasive neuro-developmental disorder which is caused, in the vast majority of cases, by a sporadic mutation in the Methyl-CpG-binding protein-2 (MeCP2) gene. This is a transcriptional activator/repressor with presumed pleiotropic activities. The broad tissue expression of MeCP2 suggests that it may be involved in several metabolic pathways, but the molecular mechanisms which provoke the onset and progression of the syndrome are largely unknown. In this paper, we report that primary fibroblasts that have been isolated from RTT patients display a defective formation of autophagosomes under conditions of nutrient starvation and that the mature Red Blood Cells of some RTT patients retain mitochondria. Moreover, we provide evidence regarding the accumulation of the p62/SQSTM1 protein and ubiquitin-aggregated structures in the cerebellum of Mecp2 knockout mouse model ( Mecp2 −/ y ) during transition from the non-symptomatic to the symptomatic stage of the disease. Hence, we propose that a defective autophagy could be involved in the RTT clinical phenotype, which introduces new molecular perspectives in the pathogenesis of the syndrome.

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          Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

          Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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            Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

            Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.
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              Essential role for Nix in autophagic maturation of erythroid cells.

              Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation. Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation, the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L), in the regulation of erythroid maturation through mitochondrial autophagy. Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix(-/-) mice exhibited mitochondrial retention and reduced lifespan in vivo. Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. Deficiency in Nix inhibited the loss of mitochondrial membrane potential (DeltaPsi(m)), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of DeltaPsi(m) and restored the sequestration of mitochondria into autophagosomes in Nix(-/-) erythroid cells. These results suggest that Nix-dependent loss of DeltaPsi(m) is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythroid maturation and results in anaemia. Our study may also provide insights into molecular mechanisms underlying mitochondrial quality control involving mitochondrial autophagy.
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                Author and article information

                Contributors
                stefano.marini@uniroma2.it
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                26 September 2017
                26 September 2017
                2017
                : 7
                : 12297
                Affiliations
                [1 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Clinical Sciences and Translational Medicine, , University of Rome Tor Vergata, ; Rome, Italy
                [2 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Biomedicine and Prevention, , University of Rome Tor Vergata, ; Rome, Italy
                [3 ]ISNI 0000 0004 1757 2064, GRID grid.8484.0, Department of Life Sciences and Biotechnology, , University of Ferrara, ; Ferrara, Italy
                [4 ]ISNI 0000 0001 2173 6074, GRID grid.40803.3f, Plant for Human Health Institute, North Carolina State University, ; Kannapolis, NC USA
                [5 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Medicine of Systems, University of Tor Vergata, ; Rome, Italy
                [6 ]ISNI 0000 0001 0692 3437, GRID grid.417778.a, Neuroimmunology Unit, Santa Lucia Foundation, ; Rome, Italy
                [7 ]ISNI 0000 0004 1758 2860, GRID grid.419869.b, Institute of Genetics and Biophysics “A.Buzzati Traverso”, ; Naples, Italy
                [8 ]ISNI 0000 0004 1760 3561, GRID grid.419543.e, IRCCS Neuromed, ; Pozzuoli, (Is) Italy
                [9 ]University Department of Pediatrics, Bambino Gesù Children’s Hospital, University of Rome Tor Vergata, Rome, Italy
                [10 ]ISNI 0000 0004 1759 0844, GRID grid.411477.0, Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), ; Siena, Italy
                Article
                12069
                10.1038/s41598-017-12069-0
                5614985
                28951555
                66d8fbf7-0ca9-4208-9141-732c31c53c01
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 November 2016
                : 4 September 2017
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