TDP-43 is intercellularly transmitted across axon terminals.

Abstract

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.

• Authors: 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, Jochen H Weishaupt
• Journal: The Journal of cell biology (J Cell Biol) Vol. 211 Issue 4 Pg. 897-911 (Nov 23 2015) ISSN: 1540-8140 [Electronic] United States
• PMID: 26598621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Feiler et al.

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human

Topics

• Amyotrophic Lateral Sclerosis (metabolism)
• Animals
• DNA-Binding Proteins (metabolism)
• Exosomes (metabolism)
• HEK293 Cells
• Humans
• Mice, Inbred C57BL
• Neurons (metabolism)
• Protein Multimerization
• Protein Transport
• Synaptic Transmission