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High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis
Fragola G, Weeks RD, Wolter J, Bryan AF, Kapfer KN, Tian X, Necarsulmer JC, Evangelista BA et al.. bioRxiv, 2026-08-19
Topic: Air pollution and environmental exposures
Transactive response DNA-binding protein 43 (TDP-43) aggregation and loss of function are hallmark features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among other neurodegenerative diseases. Despite epidemiological evidence linking environmental exposures to neurodegeneration, few toxicants have been directly associated with neurodegeneration. Here, we performed a high-content imaging screen, using a library of over a thousand chemical compounds that are considered high risk for human exposure and identified 21 toxicants that drive TDP-43 aggregation. Among the top chemical hits, five belonged to the dithiocarbamate (DTC) class of thiol-reactive compounds including the agricultural pesticides thiram and ziram. Thiram directly promoted TDP-43 cysteine oxidation and intermolecular crosslinking, whereas ziram induced TDP-43 aggregation via zinc imbalance and enhanced oxidative stress, suggesting DTCs disrupt redox homeostasis. In primary neurons and human iPSC-derived neurons, DTCs led to TDP-43 aggregation and prominent splicing defects consistent with loss of TDP-43 function. In exposed zebrafish, DTCs impaired TDP-43 function and triggered widespread transcriptional changes reflected by perturbed stress response and metabolic signatures. By combining TDP-43 loss of function mutations with chemical exposures, we observed accelerated TDP-43 loss of function and chemical-induced aggregation, supporting a multiple hit mechanism driving TDP-43 dysfunction. Together, these findings identify DTCs, particularly those used as agricultural pesticides, as dominant modifiers of TDP-43 proteostasis and identify redox imbalance and zinc homeostasis as a central molecular mechanism linking toxicant exposure to TDP-43 proteinopathy.
Key findings
- Despite epidemiological evidence linking environmental exposures to neurodegeneration, few toxicants have been directly associated with neurodegeneration.
- By combining TDP-43 loss of function mutations with chemical exposures, we observed accelerated TDP-43 loss of function and chemical-induced aggregation, supporting a multiple hit mechanism driving TDP-43 dysfunction.
- Together, these findings identify DTCs, particularly those used as agricultural pesticides, as dominant modifiers of TDP-43 proteostasis and identify redox imbalance and zinc homeostasis as a central molecular mechanism linking toxicant exposure to TDP-43 proteinopathy.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Fragola, G., Weeks, R. D., Wolter, J., Bryan, A. F., Kapfer, K. N., Tian, X., et al. (2026). High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis. bioRxiv. https://doi.org/10.64898/2026.08.14.741835
Vancouver
Fragola G, Weeks RD, Wolter J, Bryan AF, Kapfer KN, Tian X, et al. High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis. bioRxiv. 2026. doi:10.64898/2026.08.14.741835.
BibTeX
@article{fragola2026-76961fd3,
author = {Fragola, G. and Weeks, R. D. and Wolter, J. and Bryan, A. F. and Kapfer, K. N. and Tian, X. and Necarsulmer, J. C. and Evangelista, B. A. and others},
title = {{High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.08.14.741835},
url = {https://doi.org/10.64898/2026.08.14.741835}
}
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