Journal
JOURNAL OF CELL BIOLOGY
Volume 211, Issue 4, Pages 897-911Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201504057
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Funding
- German Federal Ministry of Education and Research (German network for ALS [MND-NET])
- Charcot Foundation for ALS Research
- virtual Helmholtz Institute
- Deutsche Forschungsgemeinschaft-Swabian ALS Registry
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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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