A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity

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• dc.contributor.author Picón-Pagès, Pol
• dc.contributor.author Bosch Morató, Mònica, 1986-
• dc.contributor.author Subirana, Laia
• dc.contributor.author Rubio-Moscardó, Francisca
• dc.contributor.author Guivernau Almazán, Biuse, 1988-
• dc.contributor.author Fanlo-Ucar, Hugo
• dc.contributor.author Zeylan, Melisa Ece
• dc.contributor.author Senyuz, Simge
• dc.contributor.author Herrera-Fernández, Víctor
• dc.contributor.author Vicente García, Rubén, 1978-
• dc.contributor.author Fernández-Fernández, José Manuel, 1967-
• dc.contributor.author García Ojalvo, Jordi
• dc.contributor.author Gursoy, Attila
• dc.contributor.author Keskin, Ozlem
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Posas Garriga, Francesc
• dc.contributor.author Nadal Clanchet, Eulàlia de
• dc.contributor.author Muñoz López, Francisco José, 1964-
• dc.date.accessioned 2023-01-25T07:32:51Z
• dc.date.available 2023-01-25T07:32:51Z
• dc.date.issued 2023
• dc.description.abstract Alzheimer's disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1-42. We identified 81 mammalian orthologue genes that enhance Aβ1-42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAβ1-42, whereas SURF4 overexpression induced Aβ1-42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ1-42 neurotoxicity by decreasing SOCE activity.
• dc.description.sponsorship This work was supported by the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación plus European Regional Development Fund (FEDER Funds) through grants PID2020-117691RB-I00/AEI/10.13039/501100011033 (FJM), SAF2017-83372-R (FJM), PID2020-113203RB-I00 (BO), PID2021-127311NB-I00 (JGO), RTI2018-094809-B-I00 (JMF-F) and PID2019-106755RB-I00 (RV). The laboratories of FP and EdN are supported by a coordinated grant from the Ministry of Science, Innovation, and Universities (PID2021-124723NB-C21/C22 and FEDER) and the Government of Catalonia (2017 SGR 799). This work was also funded by the Spanish Institute of Health Carlos III by project reference AC20/00009-FEDER/UE and European Research Area Net (ERANET) ERA-CVD_JTC2020-015 (JGO), TÜBİTAK UPAG ERA-CVD 220N252 (AG), the “María de Maeztu Programme” for Units of Excellence in Research and Development (R&D; award CEX2018-000792-M) and Fundación QUAES through Cátedra QUAES-UPF de Biomedicina e Ingeniería Biomédica. We gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia. FP, EdN and JGO also acknowledge the support from the Institució Catalana de Recerca i Estudis Avançats (ICREA) Academia programme (Government of Catalonia).
• dc.format.mimetype application/pdf
• dc.identifier.citation Picón-Pagès P, Bosch-Morató M, Subirana L, Rubio-Moscardó F, Guivernau B, Fanlo-Ucar H, Zeylan ME, Senyuz S, Herrera-Fernández V, Vicente R, Fernández-Fernández JM, García-Ojalvo J, Gursoy A, Keskin O, Oliva B, Posas F, de Nadal E, Muñoz FJ. A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity. Int J Mol Sci. 2023 Jan 9;24(2):1278. DOI: 10.3390/ijms24021278
• dc.identifier.doi http://dx.doi.org/10.3390/ijms24021278
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/55433
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2023 Jan 9;24(2):1278
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117691RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113203RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-127311NB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094809-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106755RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C22
• dc.rights © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Alzheimer’s disease
• dc.subject.keyword SOCE
• dc.subject.keyword SURF4
• dc.subject.keyword Amyloid beta-peptide
• dc.subject.keyword Calcium
• dc.subject.keyword Genome-wide screening
• dc.title A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion