A novel C. elegans model for MAPT/Tau spreading reveals genes critical for endolysosomal integrity and seeded MAPT/Tau aggregation
Carl Alexander Sandhof, Nicole Martin, Jessica Tittelmeier, Annabelle Schlueter, Martina Pezzali, David C. Schoendorf, Timo Lange, Peter P. Reinhardt et al.. Autophagy, 2025-08-25
Topic: Brain proteins, microglia and lab models
The spreading of MAPT/Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of MAPT/Tau aggregates, releasing the transferred MAPT/Tau species into the cytosol where they can promote the aggregation of endogenous MAPT/Tau. However, understanding of the cellular pathways involved in this process remains limited. In this study, we investigated cellular pathways that prevent endolysosomal vesicle rupture. We established a new C. elegans model of MAPT/Tau spreading by introducing an mCherry-labeled, disease-associated aggregation-prone fragment of human MAPT/Tau (F3ΔK281:mCh) into the six touch receptor neurons. F3ΔK281:mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this MAPT/Tau fragment. In addition, its intercellular transmission compromised the endolysosomal system in receiving hypodermal cells. Using this model, we conducted an unbiased genome-wide RNAi screen and identified 59 genes critical for maintaining endolysosomal integrity. GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism. Silencing of selected conserved genes exacerbated seeded MAPT/Tau aggregation in a human induced pluripotent stem cell (hiPSC)-derived cortical neuron model and triggered endolysosomal rupture in HEK293T cells, confirming the crucial role of endolysosomal damage in seeded MAPT/Tau aggregation. Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity. These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of MAPT/Tau pathology.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Sandhof, C. A., Martin, N., Tittelmeier, J., Schlueter, A., Pezzali, M., Schoendorf, D. C., et al. (2025). A novel C. elegans model for MAPT/Tau spreading reveals genes critical for endolysosomal integrity and seeded MAPT/Tau aggregation. Autophagy. https://doi.org/10.1080/15548627.2025.2551676
Vancouver
Sandhof CA, Martin N, Tittelmeier J, Schlueter A, Pezzali M, Schoendorf DC, et al. A novel C. elegans model for MAPT/Tau spreading reveals genes critical for endolysosomal integrity and seeded MAPT/Tau aggregation. Autophagy. 2025. doi:10.1080/15548627.2025.2551676. PMID: 40851193.
BibTeX
@article{sandhof2025-40851193,
author = {Sandhof, Carl Alexander and Martin, Nicole and Tittelmeier, Jessica and Schlueter, Annabelle and Pezzali, Martina and Schoendorf, David C. and Lange, Timo and Reinhardt, Peter P. and others},
title = {{A novel C. elegans model for MAPT/Tau spreading reveals genes critical for endolysosomal integrity and seeded MAPT/Tau aggregation}},
journal = {Autophagy},
year = {2025},
doi = {10.1080/15548627.2025.2551676},
pmid = {40851193},
url = {https://doi.org/10.1080/15548627.2025.2551676}
}
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.
Key findings
- The spreading of MAPT/Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer disease and other tauopathies.
- F3ΔK281:mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this MAPT/Tau fragment.
- GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism.
- Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity.
- These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of MAPT/Tau pathology.
Why it matters
This study established a new C. elegans model of MAPT/Tau spreading and used a genome-wide RNAi screen to identify 59 genes critical for maintaining endolysosomal integrity. The findings are from a worm model and identify genes related to the ESCRT complex, ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 42/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Autophagy) |
| Journal's citation record | 2 / 4 | Autophagy: journal h-index 240 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | Laboratory or animal study (title names “c. elegans”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Carmen I. Nussbaum-Krammer: h-index 22 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40851193) |
| Free to read | 2 / 2 | Free to read |
| Total | 42 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Related
Studies in the library that share something with this one. The line above each title says what.
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Related studies in Genetics
Also tagged “phosphorylated”
732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.