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Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis
Sullivan SE, Liao M, Smith RV, White C, Lagomarsino VN, Xu J, Taga M, Bennett DA et al.. Human molecular genetics, 2019-03-01
Topic: Brain proteins, microglia and lab models
Large-scale 'omic' studies investigating the pathophysiological processes that lead to Alzheimer's disease (AD) dementia have identified an increasing number of susceptibility genes, many of which are poorly characterized and have not previously been implicated in AD. Here, we evaluated the utility of human induced pluripotent stem cell-derived neurons and astrocytes as tools to systematically test AD-relevant cellular phenotypes following perturbation of candidate genes identified by genome-wide studies. Lentiviral-mediated delivery of shRNAs was used to modulate expression of 66 genes in astrocytes and 52 genes in induced neurons. Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-β (Aβ) levels. Knockdown of AP3M2, CNN2, GSTP1, NPC1, NPC2, PSAP and SORL1 reduced interleukin-6 levels in astrocytes. Only knockdown of FERMT2 led to a reduction in the proportion of TAU that is phosphorylated. Further, CRISPR-Cas9 targeting of FERMT2 in both familial AD (fAD) and fAD-corrected human neurons validated the findings of reduced extracellular Aβ. Interestingly, FERMT2 reduction had no effect on the Aβ42:40 ratio in corrected neurons and a reduction of phospho-tau, but resulted in an elevation in Aβ42:40 ratio and no reduction in phospho-tau in fAD neurons. Taken together, this study has prioritized 15 genes as being involved in contributing to Aβ accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.
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APA 7th
Sullivan, S. E., Liao, M., Smith, R. V., White, C., Lagomarsino, V. N., Xu, J., et al. (2019). Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis. Human molecular genetics. https://doi.org/10.1093/hmg/ddy376
Vancouver
Sullivan SE, Liao M, Smith RV, White C, Lagomarsino VN, Xu J, et al. Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis. Human molecular genetics. 2019. doi:10.1093/hmg/ddy376. PMID: 30371777.
BibTeX
@article{sullivan2019-30371777,
author = {Sullivan, S. E. and Liao, M. and Smith, R. V. and White, C. and Lagomarsino, V. N. and Xu, J. and Taga, M. and Bennett, D. A. and others},
title = {{Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis}},
journal = {Human molecular genetics},
year = {2019},
doi = {10.1093/hmg/ddy376},
pmid = {30371777},
url = {https://doi.org/10.1093/hmg/ddy376}
}
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Key findings
- Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-β (Aβ) levels.
- Taken together, this study has prioritized 15 genes as being involved in contributing to Aβ accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.
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Study details
- Evidence strengthLow
How this study scored 38/100
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. 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 22 of the 58 points we could judge it on, which is 38 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 | 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 | 2 / 5 | 2019 — within 10 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 | — / 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 30371777) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 22 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 22 of the 58 points we could judge it on is 38 out of 100. |
| Total | 38 / 100 | — |
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