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TDP-43 is intercellularly transmitted across axon terminals

The Journal of cell biology, 2015-11, Vol.211 (4), p.897-911 [Peer Reviewed Journal]

2015 Feiler et al. ;2015 Feiler et al. 2015 ;ISSN: 0021-9525 ;EISSN: 1540-8140 ;DOI: 10.1083/jcb.201504057 ;PMID: 26598621

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Title:
TDP-43 is intercellularly transmitted across axon terminals
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
Subjects: Amyotrophic Lateral Sclerosis - metabolism ; Animals ; DNA-Binding Proteins - metabolism ; Exosomes - metabolism ; HEK293 Cells ; Humans ; Mice, Inbred C57BL ; Neurons - metabolism ; Neurons - secretion ; Protein Multimerization ; Protein Transport ; Synaptic Transmission
Is Part Of: The Journal of cell biology, 2015-11, Vol.211 (4), p.897-911
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.
Publisher: United States: The Rockefeller University Press
Language: English
Identifier: ISSN: 0021-9525
EISSN: 1540-8140
DOI: 10.1083/jcb.201504057
PMID: 26598621
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central

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TDP-43 is intercellularly transmitted across axon terminals

2015 Feiler et al. ;2015 Feiler et al. 2015 ;ISSN: 0021-9525 ;EISSN: 1540-8140 ;DOI: 10.1083/jcb.201504057 ;PMID: 26598621

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