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TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging
Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, Mifflin L, Pan L et al.. Cell, 2018-08-23
Topic: Brain proteins, microglia and lab models
Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1 -/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1 +/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
Key findings
- Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration.
- We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1 -/- mice is dependent on RIPK1 kinase activity.
- In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression.
- We show that in Tbk1 +/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1.
- Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
Why it matters
This mouse and human brain study found that aging reduces TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD, and that these features were blocked upon inhibition of RIPK1 in mice. These are early animal and tissue findings about ALS and frontotemporal dementia, not a treatment, cure or prevention for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 54/100
Published in a peer-reviewed 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 | 7 / 10 | Tier 3 — peer-reviewed journal (Cell) |
| Journal's citation record | 4 / 4 | Cell: journal h-index 1,220 (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 | 2 / 5 | 2018 — within 10 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 | 6 / 7 | Cited 459 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 45.9 citations a year over 10 year(s) since 2018 |
| Impact for its field and year | 4 / 6 | Cited 12.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 5 other studies in this library |
| Still being cited | 3 / 4 | Cited 183 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Junying Yuan: h-index 120 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30146158) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
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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
Xu, D., Jin, T., Zhu, H., Chen, H., Ofengeim, D., Zou, C., et al. (2018). TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. https://doi.org/10.1016/j.cell.2018.07.041
Vancouver
Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, et al. TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. 2018. doi:10.1016/j.cell.2018.07.041. PMID: 30146158.
BibTeX
@article{xu2018-30146158,
author = {Xu, D. and Jin, T. and Zhu, H. and Chen, H. and Ofengeim, D. and Zou, C. and Mifflin, L. and Pan, L. and others},
title = {{TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging}},
journal = {Cell},
year = {2018},
doi = {10.1016/j.cell.2018.07.041},
pmid = {30146158},
url = {https://doi.org/10.1016/j.cell.2018.07.041}
}
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