TDP-43 is intercellularly transmitted across axon terminals

• Verfasst von: Feiler, Marisa S. [VerfasserIn]
• Verfasst von: Strobel, Benjamin [VerfasserIn]
• Verfasst von: Freischmidt, Axel [VerfasserIn]
• Verfasst von: Helferich, Anika Marie [VerfasserIn]
• Verfasst von: Kappel, Julia [VerfasserIn]
• Verfasst von: Brewer, Bryson M. [VerfasserIn]
• Verfasst von: Li, Deyu [VerfasserIn]
• Verfasst von: Thal, Dietmar R. [VerfasserIn]
• Verfasst von: Walther, Paul [VerfasserIn]
• Verfasst von: Ludolph, Albert C. [VerfasserIn]
• Verfasst von: Danzer, Karin M. [VerfasserIn]
• Verfasst von: Weishaupt, Jochen H. [VerfasserIn]
• Titel: TDP-43 is intercellularly transmitted across axon terminals
• Verf.angabe: 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, and Jochen H. Weishaupt
• E-Jahr: 2015
• Jahr: November 23, 2015
• Umfang: 15 S.
• Teil: volume:211
• Teil: year:2015
• Teil: number:4
• Teil: pages:897-911
• Teil: extent:15
• Fussnoten: Gesehen am 16.06.2021
• Titel Quelle: Enthalten in: The journal of cell biology
• Ort Quelle: New York, NY : Rockefeller Univ. Press, 1962
• Jahr Quelle: 2015
• Band/Heft Quelle: 211(2015), 4, Seite 897-911
• ISSN Quelle: 1540-8140
• DOI: doi:10.1083/jcb.201504057
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 176065096X

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.