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J Cell Biol. 2015 Nov 23;211(4):897-911. doi: 10.1083/jcb.201504057.

TDP-43 is intercellularly transmitted across axon terminals.

Author information

  • 1Department of Neurology, Ulm University, Ulm 89081, Germany.
  • 2Target Discovery Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
  • 3Department of Mechanical Engineering, Vanderbilt University, Nashville, TN 37212.
  • 4Laboratory for Neuropathology, Institute of Pathology, Ulm University, 89081 Ulm, Germany.
  • 5Central Facility for Electron Microscopy, Ulm University, 89081 Ulm, Germany.
  • 6Department of Neurology, Ulm University, Ulm 89081, Germany Jochen.Weishaupt@uni-ulm.de.

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.

PMID:
26598621
PMCID:
PMC4657165
DOI:
10.1083/jcb.201504057
[PubMed - indexed for MEDLINE]
Free PMC Article
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