TDP-43 is intercellularly transmitted across axon terminals

Feiler, Marisa S.; Strobel, Benjamin; Freischmidt, Axel; Helferich, Anika M.; Kappel, Julia; Brewer, Bryson M.; Li, Deyu; Thal, Dietmar Rudolf; Walther, Paul; Ludolph, Albert C.; Danzer, Karin M; Weishaupt, Jochen H.

doi:10.1083/jcb.201504057

Cited by 266 publications

(302 citation statements)

References 46 publications

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“…23 It is likely that this mode of uptake is not specific to TDP-43 but to protein aggregates in general. 24,25 Similarly, both conditioned media containing TDP-43 from cultured cells, and homogenates from ALS patient brains, have been shown to interact with cell produced TDP-43 using a split luciferase reporter 11 and transduced TDP-43 aggregates from brain material has been shown to increase cell produced TDP-43 aggregation via western blot. 8,9 It is interesting to note that the transmission rates are low in these experiments.…”

Section: Discussionmentioning

confidence: 99%

“…10 An additional study presented evidence to suggest that TDP-43 can transfer between HEK293 cells and primary cortical mouse neurons and interact with endogenous TDP-43 in recipient cells. 11 More recently, it was observed that TDP-43 fibrils formed from short C-terminal derived peptides triggered the seeddependent aggregation of wild type TDP-43 (TDP-43 WT ) or TDP-43 lacking a nuclear localization signal in SH-SY5Y cells resulting in different peptides sequences of TDP-43 producing fibrils with distinct biochemical properties reminiscent of prion strains. 12 Recently a novel method for quantifying protein inclusions was described.…”

Section: Introductionmentioning

confidence: 99%

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Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Zeineddine

Whiten

Farrawell

et al. 2017

Prion

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ABSTRACT. Amyotrophic lateral sclerosis is a devastating neuromuscular degenerative disease characterized by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology including TAR DNA-binding protein of 43 kDa (TDP-43) aggregates. Previous work suggests that TDP-43 can move between cells. Here we used a novel flow cytometry technique (FloIT) to analyze TDP-43 inclusions and propagation. When cells were transfected to express either mutant G294A TDP-43 fused to GFP or wild type TDP-43fused to tomato red and then co-cultured, flow cytometry detected intact cells containing both fusion proteins and using FloIT detected an increase in the numbers of inclusions in lysates from cells expressing wild type TDP-43-tomato. Furthermore, in this same model, FloIT analyses detected inclusions containing both fusion proteins. These results imply the transfer of TDP-43 fusion proteins between cells and that this process can increase aggregation of wild-type TDP-43 by a mechanism involving co-aggregation with G294A TDP-43.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Zeineddine

Whiten

Farrawell

et al. 2017

Prion

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“…A recent study provides evidence for a primarily microvesicular intercellular spread of TDP-43 aggregates [203], and both neuronal and astroglial MVs have been implicated in the propagation of pathogenic misfolded SOD1. In vitro, motor neuron NSC-34 cells overexpressing wild type and mutant SOD1 secreted this protein via exosomes [204].…”

Section: Microglia May Drive Als Pathophysiologymentioning

confidence: 99%

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Rodrı́guez¹,

Mahy²

2016

CMC

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“…By monitoring the levels of TDP-43 oligomers in vitro, TDP-43 has been found to communicate through the axon in the cell by synaptic and microencapsulated uptake [10] . With the help of nuclear magnetic resonance, simulation and microscopy, a sub-region has been found cooperatively but transiently to be folded into an a-Helical form that mediates TDP-43 phase separation [11] .…”

Section: Normal Tdp-43 and Its Functionmentioning

confidence: 99%

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

Dong¹,

Chen²

2018

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Deposition of intracellular ubiquitin inclusion in motor neurons is one of the leading pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). The transactive response DNA binding protein-43 (TDP-43) is the main component of intracellular ubiquitin inclusion bodies in pathological deposits. TDP-43 is mainly distributed in the nucleus of neurons, and participates in nuclear RNA transcription, alternative splicing and mRNA stability regulation. The tardbp , as a coding gene, provides instructions for making TDP-43. After post-translational modification, the pathological TDP-43 induces pathological deposition in cells and is associated with neurodegenerative diseases, which is similar to tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease. The pathogenic tardbp mutation can affect the localization of reverse transcription in the cell. This review summarizes the mechanisms underlying the pathogenesis of ALS by ubiquitination of TDP-43 protein.

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TDP-43 is intercellularly transmitted across axon terminals

Abstract: A protein complementation assay quantifying TDP-43 oligomerization in living neurons shows microvesicular and bidirectional synaptic transmission of TDP-43 and TDP-43 seeding activity in human ALS postmortem brain tissue.

Cited by 266 publications

References 46 publications

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

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