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A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia
Farzaneh Sadat Mirfakhar, Jacob A. Marsh, Chihiro Sato, Kylie J. Schache, Miguel Minaya, Roland E. Dolle, Stephen C. Pak, Gary A. Silverman et al.. Nature Communications, 2026-03-31
Topic: Brain proteins, microglia and lab models
Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.
Key findings
- Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.
Why it matters
In human neurons, a disease-causing mutation in the MAPT gene was sufficient to disrupt multiple steps of the autophagy-lysosome pathway and cause Tau to accumulate in dysfunctional lysosomes. Pharmacological enhancement of autophagy improved cargo clearance and lowered Tau levels in this cell model, suggesting that boosting autophagy may help restore Tau homeostasis in tauopathies, but this is early laboratory work.
Study details
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (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 | 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 | 2 / 7 | Cited 8 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 5 / 6 | Cited 33.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Celeste M M. Karch: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41916975) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-026-70473-5
- PubMed: 41916975
- Original source →
- Free full text: Nature Communications →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Mirfakhar, F. S., Marsh, J. A., Sato, C., Schache, K. J., Minaya, M., Dolle, R. E., et al. (2026). A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia. Nature Communications. https://doi.org/10.1038/s41467-026-70473-5
Vancouver
Mirfakhar FS, Marsh JA, Sato C, Schache KJ, Minaya M, Dolle RE, et al. A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia. Nature Communications. 2026. doi:10.1038/s41467-026-70473-5. PMID: 41916975.
BibTeX
@article{mirfakhar2026-41916975,
author = {Mirfakhar, Farzaneh Sadat and Marsh, Jacob A. and Sato, Chihiro and Schache, Kylie J. and Minaya, Miguel and Dolle, Roland E. and Pak, Stephen C. and Silverman, Gary A. and others},
title = {{A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia}},
journal = {Nature Communications},
year = {2026},
doi = {10.1038/s41467-026-70473-5},
pmid = {41916975},
url = {https://doi.org/10.1038/s41467-026-70473-5}
}
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