Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome.

Autor: Botté A; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France., Lainé J; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.; Sorbonne Université, Département de Physiologie, Hôpital de la Pitié-Salpêtrière, Paris, France., Xicota L; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France., Heiligenstein X; CryoCapCell, 155 Bd de l'hôpital, 75013, Paris, France.; Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, France., Fontaine G; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France., Kasri A; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France., Rivals I; Equipe de Statistique Appliquée, ESPCI Paris, PSL Research University, UMRS 1158, Paris, France., Goh P; The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK., Faklaris O; ImagoSeine Imaging Core Facility, Institut Jacques Monod, CNRS UMR7592, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France., Cossec JC; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France., Morel E; Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, Paris, France., Rebillat AS; Institut Jérôme Lejeune, Paris, France., Nizetic D; The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore., Raposo G; Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, France., Potier MC; Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France. marie-claude.potier@upmc.fr.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2020 Jun 24; Vol. 8 (1), pp. 89. Date of Electronic Publication: 2020 Jun 24.
DOI: 10.1186/s40478-020-00956-z
Abstrakt: Enlarged early endosomes have been visualized in Alzheimer's disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS.By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13-19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS. However, EEA1-positive structures imaged by TEM or SR-SIM after chemical fixation had a normal size but appeared clustered. In order to disentangle these discrepancies, we imaged optimally preserved High Pressure Freezing (HPF)-vitrified DS fibroblasts by TEM and found that early endosomes were 75% denser but remained normal-sized.RNA sequencing of DS and euploid fibroblasts revealed a subgroup of differentially-expressed genes related to cargo sorting at multivesicular bodies (MVBs). We thus studied the dynamics of endocytosis, recycling and MVB-dependent degradation in DS fibroblasts. We found no change in endocytosis, increased recycling and delayed degradation, suggesting a "traffic jam" in the endosomal compartment.Finally, we show that the phosphoinositide PI (3) P, involved in early endosome fusion, is decreased in DS fibroblasts, unveiling a new mechanism for endosomal dysfunctions in DS and a target for pharmacotherapy.
Databáze: MEDLINE
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