title: 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.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Feiler
authors.affiliation: Target Discovery Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Strobel
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Freischmidt
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Anika M
authors.initials: AM
authors.lastname: Helferich
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kappel
authors.affiliation: Department of Mechanical Engineering, Vanderbilt University, Nashville, TN 37212.
authors.forename: Bryson M
authors.initials: BM
authors.lastname: Brewer
authors.affiliation: Department of Mechanical Engineering, Vanderbilt University, Nashville, TN 37212.
authors.forename: Deyu
authors.initials: D
authors.lastname: Li
authors.affiliation: Laboratory for Neuropathology, Institute of Pathology, Ulm University, 89081 Ulm, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: Central Facility for Electron Microscopy, Ulm University, 89081 Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.affiliation: Department of Neurology, Ulm University, Ulm 89081, Germany Jochen.Weishaupt@uni-ulm.de.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport; D009435:Synaptic Transmission
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human