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

Alzheimer's disease (AD) is known to be caused by amyloid beta-peptide (A beta) misfolded into beta-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in A beta toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing A beta(1-42). We identified 81 mammalian orthologue genes that enhance A beta(1-42) 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 A beta oligomers (oA beta). 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 oA beta(1-42), whereas SURF4 overexpression induced A beta(1-42) cytotoxicity. In summary, we identified new enhancer and protective activities for A beta toxicity and showed that SURF4 contributes to oA beta(1-42) neurotoxicity by decreasing SOCE activity.
Spanish Ministry of Science and Innovation; Agencia Estatal de Investigacion; Europen Union (EU); European Regional Development Fund (FEDER Funds); Ministry of Science, Innovation, and Universities; Government of Catalonia; Spanish Institute of Health Carlos III; European Research Area Net (ERANET); Scientific and Technological Research Council of Turkey (TÜBİTAK); TÜBİTAK UPAG ERA-CVD; ""Maria de Maeztu Programme"" for Units of Excellence in Research and Development; Fundacion QUAES; Catedra QUAES-UPF de Biomedicina e Ingenieria Biomedica; Ministry of Science, Innovation and Universities; Centres of Excellence Severo Ochoa Award; CERCA Programme of the Government of Catalonia; FP; EdN; JGO; Institucio Catalana de Recerca i Estudis Avancats (ICREA) Academia Programme