Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms
Joshua M Shulman, Selina H. Imboywa, Νικόλαος Γιαγτζόγλου, Martin P. Powers, Yanhui Hu, Danelle Devenport, Portia I. Chipendo, Lori Beth Chibnik et al.. Human Molecular Genetics, 2013-09-25
Topic: Disease mechanisms in lab and animal studies
Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (P < 10(-4)) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.
Key findings
- Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 67/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size and effect reported 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 39 of the 58 points we could judge it on, which is 67 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Human Molecular Genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — 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 | Laboratory or animal study (title names “drosophila”) — scores zero |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| 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 24067533) |
| Free to read | 2 / 2 | Free to read |
| Points | 39 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 39 of the 58 points we could judge it on is 67 out of 100. |
| Total | 67 / 100 | — |
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APA 7th
Shulman, J. M., Imboywa, S. H., Γιαγτζόγλου, Ν., Powers, M. P., Hu, Y., Devenport, D., et al. (2013). Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddt478
Vancouver
Shulman JM, Imboywa SH, Γιαγτζόγλου Ν, Powers MP, Hu Y, Devenport D, et al. Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Human Molecular Genetics. 2013. doi:10.1093/hmg/ddt478. PMID: 24067533.
BibTeX
@article{shulman2013-24067533,
author = {Shulman, Joshua M and Imboywa, Selina H. and Γιαγτζόγλου, Νικόλαος and Powers, Martin P. and Hu, Yanhui and Devenport, Danelle and Chipendo, Portia I. and Chibnik, Lori Beth and others},
title = {{Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms}},
journal = {Human Molecular Genetics},
year = {2013},
doi = {10.1093/hmg/ddt478},
pmid = {24067533},
url = {https://doi.org/10.1093/hmg/ddt478}
}
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