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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| Hauptverfasser: | , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
November 23, 2015
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| In: |
The journal of cell biology
Year: 2015, Jahrgang: 211, Heft: 4, Pages: 897-911 |
| ISSN: | 1540-8140 |
| DOI: | 10.1083/jcb.201504057 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1083/jcb.201504057 |
| Verfasserangaben: | Marisa S. Feiler, Benjamin Strobel, Axel Freischmidt, Anika M. Helferich, Julia Kappel, Bryson M. Brewer, Deyu Li, Dietmar R. Thal, Paul Walther, Albert C. Ludolph, Karin M. Danzer, and Jochen H. Weishaupt |
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| 520 | |a 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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