TDP-43 is intercellularly transmitted across axon terminals
Open accessAbstract
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.
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Pathological TDP-43 can be transferred between cells in culture, leading to seeding and pathological mislocalization in recipient cells.
“Elegant experiments have demonstrated that pathological TDP-43 can be transferred between cells in culture (Feiler et al. 2015, Shimonaka et al. 2016), leading to seeding and pathological mislocalization in recipient cells.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Feiler et al. 2015
The Results section on TDP-43 oligomerization in recipient cells reports that cell-culture-derived TDP-43 was taken up and triggered oligomerization; the Discussion also reports seeding activity and granule formation in target cells. Feiler et al. do not demonstrate pathological mislocalization of the recipient cells’ TDP-43. The Introduction attributes nuclear-to-cytoplasmic redistribution to Zhu et al. (2014). (LLM, conf=0.85)
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- Authors
- Feiler, M. S., Strobel, B., Freischmidt, A., Helferich, A. M., Kappel, J., Brewer, B. M., Li, D., Thal, D. R., Walther, P., Ludolph, A. C., Danzer, K. M., & Weishaupt, J. H.
- Affiliations
- Universität Ulm (DE)
- Boehringer Ingelheim (Germany) (DE)
- Vanderbilt University (US)
- Corresponding author
- Weishaupt, Jochen H.
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2015-11-23
- Volume
- 211
- Issue
- 4
- Pages
- 897-911
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC4657165
- OpenAlex
- W2174491776
- Cited by
- 329
- References
- 48
- Citations by year
- 2026: 16 · 2025: 35 · 2024: 22 · 2023: 31 · 2022: 33 · 2021: 39 · 2020: 35 · 2019: 30 · 2018: 29 · 2017: 28 · 2016: 30 · 2015: 1
- FWCI
- 20.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- TDP-43, amyotrophic lateral sclerosis, intercellular protein transfer, prion-like seeding, microvesicles, exosomes, axon terminals, protein complementation assay, oligomerization, neurodegeneration
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Humans, Mice, Inbred C57BL, Synaptic Transmission, Neurons, Protein Transport, Exosomes, Protein Multimerization, HEK293 Cells
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