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Title: | Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome | Authors: | Botté, Alexandra Lainé, Jeanne Xicota, Laura Heiligenstein, Xavier Fontaine, Gaëlle Kasri, Amal Rivals, Isabelle Goh, Pollyanna Faklaris, Orestis Cossec, Jack-Christophe Morel, Etienne Rebillat, Anne-Sophie Nizetic, Dean Raposo, Graça Potier, Marie-Claude |
Keywords: | Science::Medicine | Issue Date: | 2020 | Source: | Botté, A., Lainé, J., Xicota, L., Heiligenstein, X., Fontaine, G., Kasri, A., Rivals, I., Goh, P., Faklaris, O., Cossec, J., Morel, E., Rebillat, A., Nizetic, D., Raposo, G. & Potier, M. (2020). Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome. Acta Neuropathologica Communications, 8(1). https://dx.doi.org/10.1186/s40478-020-00956-z | Project: | NMRC/CS-IRG/1438/2015 | Journal: | Acta Neuropathologica Communications | Abstract: | 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. | URI: | https://hdl.handle.net/10356/148651 | ISSN: | 2051-5960 | DOI: | 10.1186/s40478-020-00956-z | Schools: | Lee Kong Chian School of Medicine (LKCMedicine) | Rights: | © 2020 The Author(s). 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | LKCMedicine Journal Articles |
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