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Human progranulin-expressing mice as a novel tool for the development of progranulin-modulating therapeutics
Petkau TL, Life B, Lu G, Yang J, Fornes O, Wasserman W, Simpson EM, Leavitt BR.. Neurobiology of disease, 2021-02-24
Topic: Brain proteins, microglia and lab models
The granulin protein (also known as, and hereafter referred to as, progranulin) is a secreted glycoprotein that contributes to overall brain health. Heterozygous loss-of-function mutations in the gene encoding the progranulin protein (Granulin Precursor, GRN) are a common cause of familial frontotemporal dementia (FTD). Gene therapy approaches that aim to increase progranulin expression from a single wild-type allele, an area of active investigation for the potential treatment of GRN-dependent FTD, will benefit from the availability of a mouse model that expresses a genomic copy of the human GRN gene. Here we report the development and characterization of a novel mouse model that expresses the entire human GRN gene in its native genomic context as a single copy inserted into a defined locus (Hprt) in the mouse genome. We show that human and mouse progranulin are expressed in a similar tissue-specific pattern, suggesting that the two genes are regulated by similar mechanisms. Human progranulin rescues a phenotype characteristic of progranulin-null mice, the exaggerated and early deposition of the aging pigment lipofuscin in the brain, indicating that the two proteins are functionally similar. Longitudinal behavioural and neuropathological analyses revealed no significant differences between wild-type and human progranulin-overexpressing mice up to 18 months of age, providing evidence that long-term increase of progranulin levels is well tolerated in mice. Finally, we demonstrate that human progranulin expression can be increased in the brain using an antisense oligonucleotide that inhibits a known GRN-regulating micro-RNA, demonstrating that the transgene is responsive to potential gene therapy drugs. Human progranulin-expressing mice represent a novel and valuable tool to expedite the development of progranulin-modulating therapeutics.
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APA 7th
Petkau, T. L., Life, B., Lu, G., Yang, J., Fornes, O., Wasserman, W., et al. (2021). Human progranulin-expressing mice as a novel tool for the development of progranulin-modulating therapeutics. Neurobiology of disease. https://doi.org/10.1016/j.nbd.2021.105314
Vancouver
Petkau TL, Life B, Lu G, Yang J, Fornes O, Wasserman W, et al. Human progranulin-expressing mice as a novel tool for the development of progranulin-modulating therapeutics. Neurobiology of disease. 2021. doi:10.1016/j.nbd.2021.105314. PMID: 33636385.
BibTeX
@article{petkau2021-33636385,
author = {Petkau, T. L. and Life, B. and Lu, G. and Yang, J. and Fornes, O. and Wasserman, W. and Simpson, E. M. and Leavitt, B. R.},
title = {{Human progranulin-expressing mice as a novel tool for the development of progranulin-modulating therapeutics}},
journal = {Neurobiology of disease},
year = {2021},
doi = {10.1016/j.nbd.2021.105314},
pmid = {33636385},
url = {https://doi.org/10.1016/j.nbd.2021.105314}
}
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 8 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.
Key findings
- The granulin protein (also known as, and hereafter referred to as, progranulin) is a secreted glycoprotein that contributes to overall brain health.
- We show that human and mouse progranulin are expressed in a similar tissue-specific pattern, suggesting that the two genes are regulated by similar mechanisms.
- Longitudinal behavioural and neuropathological analyses revealed no significant differences between wild-type and human progranulin-overexpressing mice up to 18 months of age, providing evidence that long-term increase of progranulin levels is well tolerated in mice.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 55/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 32 of the 58 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of disease) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 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 |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33636385) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 32 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 32 of the 58 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
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