Journal Article

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

D'Esposito M., Borsellino G., Ciaccio C., Curatolo P., Galasso C., Tundo G. R., Campagnolo L., Di Pierro D., Santarone M. E., Sbardella D., Marini S., Di Cesare S., Hayek J., Orlandi A., Valacchi G., Coletta M.

2017

Overview

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.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/31 / 13/51 / 14 / 14/28 / 14/63 / 631/378/1689/1373 / 631/80/39/2346 / 82 / 82/29 / 96 / Animal / Animals / Animals; Autophagosomes; Autophagy; Cells, Cultured; Cerebellum; Disease Models, Animal; Erythrocytes; Female; Fibroblasts; Healthy Volunteers; Humans; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Primary Cell Culture; Protein Aggregates; Rett Syndrome; Sequestosome-1 Protein; Mitochondria / Autophagosome / Autophagosomes / Autophagosomes - pathology / Autophagy / Autophagy - genetics / Cells / Cells, Cultured / Cerebellum / Cerebellum - pathology / CpG islands / Cultured / Developmental disabilities / Disease Models / Disease Models, Animal / Erythrocyte / Erythrocytes / Erythrocytes - cytology / Erythrocytes - metabolism / Erythrocytes - ultrastructure / Female / Fibroblast / Fibroblasts / Healthy Volunteer / Healthy Volunteers / Human / Humanities and Social Sciences / Humans / Inbred C57BL / Knockout / Male / MeCP2 protein / Metabolic pathways / Methyl-CpG binding protein / Methyl-CpG-Binding Protein 2 / Methyl-CpG-Binding Protein 2 - genetics / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria / Molecular modelling / Multidisciplinary / Mutation / Phagocytosis / Phagosomes / Primary Cell Culture / Protein Aggregate / Protein Aggregates / Protein Aggregates - genetics / Rett Syndrome / Rett Syndrome (RTT) / Rett Syndrome - blood / Rett Syndrome - genetics / Rett Syndrome - pathology / Science / Sequestosome-1 Protein / Sequestosome-1 Protein - metabolism / Settore BIO/10 - BIOCHIMICA / Settore MED/39 - NEUROPSICHIATRIA INFANTILE / Transcription / Ubiquitin