A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

Author:

Picón-Pagès Pol,Bosch-Morató Mònica,Subirana Laia,Rubio-Moscardó Francisca,Guivernau Biuse,Fanlo-Ucar HugoORCID,Zeylan Melisa EceORCID,Senyuz Simge,Herrera-Fernández VíctorORCID,Vicente RubénORCID,Fernández-Fernández José M.ORCID,García-Ojalvo JordiORCID,Gursoy Attila,Keskin Ozlem,Oliva BaldomeroORCID,Posas Francesc,de Nadal EulàliaORCID,Muñoz Francisco J.ORCID

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.

Funder

Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación plus European Regional Development Fund

Ministry of Science, Innovation, and Universities

Government of Catalonia

Spanish Institute of Health Carlos III

European Research Area Net

Units of Excellence in Research and Development

Cátedra QUAES-UPF de Biomedicina e Ingeniería Biomédica

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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