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TDP-43 is intercellularly transmitted across axon terminals
Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequentl...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657165/ https://www.ncbi.nlm.nih.gov/pubmed/26598621 http://dx.doi.org/10.1083/jcb.201504057 |
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author | Feiler, Marisa S. Strobel, Benjamin Freischmidt, Axel Helferich, Anika M. Kappel, Julia Brewer, Bryson M. Li, Deyu Thal, Dietmar R. Walther, Paul Ludolph, Albert C. Danzer, Karin M. Weishaupt, Jochen H. |
author_facet | Feiler, Marisa S. Strobel, Benjamin Freischmidt, Axel Helferich, Anika M. Kappel, Julia Brewer, Bryson M. Li, Deyu Thal, Dietmar R. Walther, Paul Ludolph, Albert C. Danzer, Karin M. Weishaupt, Jochen H. |
author_sort | Feiler, Marisa S. |
collection | PubMed |
description | Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43–containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma “horizontal” and bidirectional “vertical” synaptic intercellular transmission and prion-like seeding of TDP-43. |
format | Online Article Text |
id | pubmed-4657165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46571652016-05-23 TDP-43 is intercellularly transmitted across axon terminals Feiler, Marisa S. Strobel, Benjamin Freischmidt, Axel Helferich, Anika M. Kappel, Julia Brewer, Bryson M. Li, Deyu Thal, Dietmar R. Walther, Paul Ludolph, Albert C. Danzer, Karin M. Weishaupt, Jochen H. J Cell Biol Research Articles Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43–containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma “horizontal” and bidirectional “vertical” synaptic intercellular transmission and prion-like seeding of TDP-43. The Rockefeller University Press 2015-11-23 /pmc/articles/PMC4657165/ /pubmed/26598621 http://dx.doi.org/10.1083/jcb.201504057 Text en © 2015 Feiler et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Feiler, Marisa S. Strobel, Benjamin Freischmidt, Axel Helferich, Anika M. Kappel, Julia Brewer, Bryson M. Li, Deyu Thal, Dietmar R. Walther, Paul Ludolph, Albert C. Danzer, Karin M. Weishaupt, Jochen H. TDP-43 is intercellularly transmitted across axon terminals |
title | TDP-43 is intercellularly transmitted across axon terminals |
title_full | TDP-43 is intercellularly transmitted across axon terminals |
title_fullStr | TDP-43 is intercellularly transmitted across axon terminals |
title_full_unstemmed | TDP-43 is intercellularly transmitted across axon terminals |
title_short | TDP-43 is intercellularly transmitted across axon terminals |
title_sort | tdp-43 is intercellularly transmitted across axon terminals |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657165/ https://www.ncbi.nlm.nih.gov/pubmed/26598621 http://dx.doi.org/10.1083/jcb.201504057 |
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