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Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ.. eLife, 2016-12-20
Topic: Brain proteins, microglia and lab models
Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function.
Key findings
- To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins.
- Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function.
- Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand.
- Additionally, the Alzheimer's risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family.
Why it matters
In lab studies of TREM2 protein and cells, mutations found in Nasu-Hakola disease were buried inside the protein and reduced its stability, so less folded TREM2 reached the cell surface. Alzheimer's disease risk variants sat on the protein's surface and affected its binding to a TREM2 ligand, which the authors describe as two distinct loss-of-function mechanisms. This is laboratory work on proteins and cells, not a study of patients, risk or treatment.
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Study details
- Evidence strengthLow
How this study scored 51/100
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 (eLife) |
| Journal's citation record | 3 / 4 | ELife: journal h-index 311 (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 | 1 / 5 | 2016 — within 20 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 | 5 / 7 | Cited 239 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 19.9 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 4 / 6 | Cited 9.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 58 other studies in this library |
| Still being cited | 3 / 4 | Cited 77 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Tom J. Brett: h-index 30 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 27995897) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
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Read the original
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 names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Kober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., et al. (2016). Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. https://doi.org/10.7554/elife.20391
Vancouver
Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. 2016. doi:10.7554/elife.20391. PMID: 27995897.
BibTeX
@article{kober2016-27995897,
author = {Kober, D. L. and Alexander-Brett, J. M. and Karch, C. M. and Cruchaga, C. and Colonna, M. and Holtzman, M. J. and Brett, T. J.},
title = {{Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms}},
journal = {eLife},
year = {2016},
doi = {10.7554/elife.20391},
pmid = {27995897},
url = {https://doi.org/10.7554/elife.20391}
}
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