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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
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.
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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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