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ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice
Isadora Lenoël, Matthieu Ribon, Félicie Lorenc, Aurélien Diebold, Clémentine Eva Philibert, David Robaldo, Manel Badsi, Julianne Perronnet et al.. Nature Communications, 2025-08-26
Topic: Brain proteins, microglia and lab models
TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we show that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction. TBK1 mutations are linked to Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal dementia (FTD), but their cell-type specific disease contributions are unclear. Here, the authors show that Tbk1 deletion from mouse microglia shifts them to an aged-like phenotype and causes social recognition deficits.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Lenoël, I., Ribon, M., Lorenc, F., Diebold, A., Philibert, C. E., Robaldo, D., et al. (2025). ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice. Nature Communications. https://doi.org/10.1038/s41467-025-63211-w
Vancouver
Lenoël I, Ribon M, Lorenc F, Diebold A, Philibert CE, Robaldo D, et al. ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice. Nature Communications. 2025. doi:10.1038/s41467-025-63211-w. PMID: 40858618.
BibTeX
@article{lenoel2025-40858618,
author = {Lenoël, Isadora and Ribon, Matthieu and Lorenc, Félicie and Diebold, Aurélien and Philibert, Clémentine Eva and Robaldo, David and Badsi, Manel and Perronnet, Julianne and others},
title = {{ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice}},
journal = {Nature Communications},
year = {2025},
doi = {10.1038/s41467-025-63211-w},
pmid = {40858618},
url = {https://doi.org/10.1038/s41467-025-63211-w}
}
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Key findings
- Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.
Why it matters
In mice, deleting Tbk1 from microglia produced an aged-like, pro-inflammatory microglial signature and caused social recognition deficits resembling frontotemporal dementia, without affecting motor neuron damage. This is animal research on ALS/FTD mechanisms and does not address treating or preventing Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 47/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomized / 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 | 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 “mice”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 9 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.7× 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 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Christian S. Lobsiger: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 14 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40858618) |
| Free to read | 2 / 2 | Free to read |
| Total | 47 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-025-63211-w
- PubMed: 40858618
- 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).
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