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Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the...

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Autores principales: Guix, Francesc X., Sannerud, Ragna, Berditchevski, Fedor, Arranz, Amaia M., Horré, Katrien, Snellinx, An, Thathiah, Amantha, Saido, Takaomi, Saito, Takashi, Rajesh, Sundaresan, Overduin, Michael, Kumar-Singh, Samir, Radaelli, Enrico, Corthout, Nikky, Colombelli, Julien, Tosi, Sébastien, Munck, Sebastian, Salas, Isabel H., Annaert, Wim, De Strooper, Bart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345265/
https://www.ncbi.nlm.nih.gov/pubmed/28279219
http://dx.doi.org/10.1186/s13024-017-0165-0
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author Guix, Francesc X.
Sannerud, Ragna
Berditchevski, Fedor
Arranz, Amaia M.
Horré, Katrien
Snellinx, An
Thathiah, Amantha
Saido, Takaomi
Saito, Takashi
Rajesh, Sundaresan
Overduin, Michael
Kumar-Singh, Samir
Radaelli, Enrico
Corthout, Nikky
Colombelli, Julien
Tosi, Sébastien
Munck, Sebastian
Salas, Isabel H.
Annaert, Wim
De Strooper, Bart
author_facet Guix, Francesc X.
Sannerud, Ragna
Berditchevski, Fedor
Arranz, Amaia M.
Horré, Katrien
Snellinx, An
Thathiah, Amantha
Saido, Takaomi
Saito, Takashi
Rajesh, Sundaresan
Overduin, Michael
Kumar-Singh, Samir
Radaelli, Enrico
Corthout, Nikky
Colombelli, Julien
Tosi, Sébastien
Munck, Sebastian
Salas, Isabel H.
Annaert, Wim
De Strooper, Bart
author_sort Guix, Francesc X.
collection PubMed
description BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. RESULTS: Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF. CONCLUSIONS: TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0165-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-53452652017-03-14 Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments Guix, Francesc X. Sannerud, Ragna Berditchevski, Fedor Arranz, Amaia M. Horré, Katrien Snellinx, An Thathiah, Amantha Saido, Takaomi Saito, Takashi Rajesh, Sundaresan Overduin, Michael Kumar-Singh, Samir Radaelli, Enrico Corthout, Nikky Colombelli, Julien Tosi, Sébastien Munck, Sebastian Salas, Isabel H. Annaert, Wim De Strooper, Bart Mol Neurodegener Research Article BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. RESULTS: Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF. CONCLUSIONS: TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0165-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-10 /pmc/articles/PMC5345265/ /pubmed/28279219 http://dx.doi.org/10.1186/s13024-017-0165-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 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.
spellingShingle Research Article
Guix, Francesc X.
Sannerud, Ragna
Berditchevski, Fedor
Arranz, Amaia M.
Horré, Katrien
Snellinx, An
Thathiah, Amantha
Saido, Takaomi
Saito, Takashi
Rajesh, Sundaresan
Overduin, Michael
Kumar-Singh, Samir
Radaelli, Enrico
Corthout, Nikky
Colombelli, Julien
Tosi, Sébastien
Munck, Sebastian
Salas, Isabel H.
Annaert, Wim
De Strooper, Bart
Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title_full Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title_fullStr Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title_full_unstemmed Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title_short Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
title_sort tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345265/
https://www.ncbi.nlm.nih.gov/pubmed/28279219
http://dx.doi.org/10.1186/s13024-017-0165-0
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