Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
Open accessAbstract
Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
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Kindlin-2 underexpression promotes recycling of full-length mature APP from endosomes to the plasma membrane, potentially favouring Aβ production.
“Kindlin-2 (product of FERMT2) underexpression has been described to promote the recycling of full-length, mature APP from early/late endosomes into the plasma membrane. This may thus favour Aβ production by increasing the pool of full-length APP likely to be cleaved by α-, β- and γ-secretases, rather than to be degraded in lysosomes [17].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [17]
The Results section reports that FERMT2 silencing promotes APP recycling through Rab4-positive endosomes, increases mature APP at the cell surface, and reduces its lysosomal degradation. The Discussion also reports increased Aβ secretion. The paper does not establish the claim’s more specific route from both early and late endosomes to the plasma membrane. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHigh-content screening identified numerous FA pathway members, including Kindlin-2, as modulators of APP metabolism.
“Importantly, high-content screening also identified numerous FA pathway members—including Kindlin-2—as modulators of APP metabolism, highlighting the relevance of the core FA proteins to the AD process [17].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [17]
Kindlin-2 is a modulator of cell surface APP levels.
“For example, Kindlin-2 expression is required for the recruitment and activation of FAK to trigger integrin signalling [100, 133], but Kindlin-2 is also a modulator of cell surface APP levels [17].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [17]
For previously reported loci, applying the same prioritization approach highlights several genes involved in APP metabolism (FERMT2, PICALM) or tau toxicity (BIN1, CD2AP, FERMT2, CASS4, PTK2B).
“For previously reported loci, applying the same prioritization approach highlights several genes, as described in Fig. 2, some of which are involved in APP metabolism (FERMT2, PICALM) or tau toxicity (BIN1, CD2AP, FERMT2, CASS4, PTK2B)98–101.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [99]
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References 28 · Cited by 75
Research works printed but not linked: 1
- [2]Bray M-A Carpenter A Imaging Platform BI of M and H 2013 Advanced Assay Development Guidelines for Image-Based High Content Screening and Analysis Eli Lilly & Company and the National Center for Advancing Translational Sciences 23469374
- Authors
- ADGC, A. D. N. I., Chapuis, J., Flaig, A., Grenier-Boley, B., Eysert, F., Pottiez, V., Deloison, G., Vandeputte, A., Ayral, A.-M., Mendes, T., Desai, S., Goate, A. M., Kauwe, J. S. K., Leroux, F., Herledan, A., Demiautte, F., Bauer, C., Checler, F., Petersen, R. C., Blennow, K., Zetterberg, H., Minthon, L., Van Deerlin, V. M., Lee, V. M.-Y., Shaw, L. M., Trojanowski, J. Q., Albert, M., Moghekar, A., O’Brien, R., Peskind, E. R., Malmanche, N., Schellenberg, G. D., Dourlen, P., Song, O.-R., Cruchaga, C., Amouyel, P., Deprez, B., Brodin, P., & Lambert, J.-C.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Brigham Young University (US)
- Mayo Clinic (US)
- Sahlgrenska University Hospital (SE)
- Lund University (SE)
- University of Pennsylvania (US)
- Johns Hopkins University (US)
- Duke University (US)
- Corresponding author
- Chapuis, Julien
- ORCID
- Chapuis, Julien
- Eysert, Fanny
- Vandeputte, Alexandre
- Ayral, Anne-Marie
- Mendes, Tiago
- Goate, Alison M.
- Leroux, Florence
- Petersen, Ronald C.
- Blennow, Kaj
- Zetterberg, Henrik
- Lee, Virginia Man-Yee
- Shaw, Leslie M.
- Trojanowski, John Q.
- Albert, Marilyn
- Moghekar, Abhay
- O’Brien, Richard
- Peskind, Elaine R.
- Schellenberg, Gerard D.
- Dourlen, Pierre
- Song, Ok-Ryul
- Cruchaga, Carlos
- Amouyel, Philippe
- Deprez, Benoit
- Brodin, Priscille
- Lambert, Jean-Charles
- Venue
- Acta Neuropathologica
- Published
- 2016-12-08
- Volume
- 133
- Issue
- 6
- Pages
- 955-966
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC5427165
- OpenAlex
- W2560005684
- Cited by
- 75
- References
- 28
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 15 · 2018: 7 · 2017: 3
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Association France Alzheimer (350)
- Alzheimer's Association (BFG-14-318355)
- National Institutes of Health (P30 AG010129, K01 AG03051, R01AG042611)
- ADC Foundation (P30 AG010124-25)
- adnik (U01 AG024904-16)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, FERMT2, APP metabolism, amyloid-beta production, cerebrospinal fluid amyloid-beta, siRNA screening
- MeSH terms
- Alzheimer Disease, Animals, Cell Membrane, Cerebral Cortex, Hippocampus, Humans, Membrane Proteins, Neoplasm Proteins, Neurons, Biomarkers, Amyloid beta-Protein Precursor, Genetic Predisposition to Disease, RNA Interference, RNA, Small Interfering, Rats, Genome-Wide Association Study, Genetic Loci, HEK293 Cells
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