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Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation
Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC et al.. Cell, 2016-04-21
Topic: Brain proteins, microglia and lab models
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
Key findings
- Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice.
- Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging.
- These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
Why it matters
In mice lacking progranulin, a gene linked to frontotemporal dementia (FTD), the brain's immune cells (microglia) made more complement proteins with age and removed more inhibitory synapses in the thalamus, which the authors link to overactive brain circuits and compulsive-like grooming. When the complement gene C1qa was also deleted, the authors report less synapse loss, neurodegeneration, abnormal behaviour and early death. The authors conclude that complement-driven synapse pruning is a major driver of progranulin-related neurodegeneration; this is a mouse study of FTD biology, not a test of any treatment or of Alzheimer's disease in people.
Study details
- Evidence strengthLow
How this study scored 57/100
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 | 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 | 6 / 7 | Cited 732 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 61.0 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 5 / 6 | Cited 34.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 34 other studies in this library |
| Still being cited | 3 / 4 | Cited 186 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Eric Jinsheng Huang: h-index 87 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 15 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 27114033) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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
Lui, H., Zhang, J., Makinson, SR., Cahill, M. K., Kelley, K. W., Huang, H. Y., et al. (2016). Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. https://doi.org/10.1016/j.cell.2016.04.001
Vancouver
Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, et al. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell. 2016. doi:10.1016/j.cell.2016.04.001. PMID: 27114033.
BibTeX
@article{lui2016-27114033,
author = {Lui, H. and Zhang, J. and Makinson, SR. and Cahill, M. K. and Kelley, K. W. and Huang, H. Y. and Shang, Y. and Oldham, M. C. and others},
title = {{Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation}},
journal = {Cell},
year = {2016},
doi = {10.1016/j.cell.2016.04.001},
pmid = {27114033},
url = {https://doi.org/10.1016/j.cell.2016.04.001}
}
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