In:
Journal of Cell Biology, Rockefeller University Press, Vol. 211, No. 4 ( 2015-11-23), p. 897-911
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.
Type of Medium:
Online Resource
ISSN:
0021-9525
,
1540-8140
DOI:
10.1083/jcb.201504057
Language:
English
Publisher:
Rockefeller University Press
Publication Date:
2015
detail.hit.zdb_id:
1421310-2
SSG:
12
