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Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin
Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A et al.. Neuron, 2010-11-01
Topic: Brain proteins, microglia and lab models
Video abstract The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1⁻/⁻ neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/⁻ mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Hu, F., Padukkavidana, T., Vægter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., et al. (2010). Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. https://doi.org/10.1016/j.neuron.2010.09.034
Vancouver
Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010. doi:10.1016/j.neuron.2010.09.034. PMID: 21092856.
BibTeX
@article{hu2010-21092856,
author = {Hu, F. and Padukkavidana, T. and Vægter, C. B. and Brady, O. A. and Zheng, Y. and Mackenzie, I. R. and Feldman, H. H. and Nykjaer, A. and others},
title = {{Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin}},
journal = {Neuron},
year = {2010},
doi = {10.1016/j.neuron.2010.09.034},
pmid = {21092856},
url = {https://doi.org/10.1016/j.neuron.2010.09.034}
}
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.
Key findings
- In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury.
- Sortilin rapidly endocytoses and delivers PGRN to lysosomes.
- Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold.
- The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/⁻ mice, and is fully normalized by Sort1 ablation.
- Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.
Why it matters
This work shows that Sortilin binds progranulin and delivers it to lysosomes, and that removing Sortilin in mice raised progranulin levels and normalized the 50% decrease seen in FTLD-TDP. It identifies a possible way to raise progranulin, but the findings are in cells and mice, not a treatment tested in patients.
Study details
- Evidence strengthLow
How this study scored 53/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (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 | 2010 — 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 558 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.0 citations a year over 18 year(s) since 2010 |
| Impact for its field and year | 4 / 6 | Cited 16.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 19 other studies in this library |
| Still being cited | 3 / 4 | Cited 96 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Stephen M. Strittmatter: h-index 104 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Yale University: institution h-index 1,927 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 21092856) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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