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 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 libr...

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Detalles Bibliográficos
Autores: Picón-Pagès, Pol, Bosch Morató, Mònica, 1986-, Subirana, Laia, Rubio-Moscardó, Francisca, Guivernau Almazán, Biuse, 1988-, Fanlo-Ucar, Hugo, Zeylan, Melisa Ece, Senyuz, Simge, Herrera-Fernández, Víctor, Vicente García, Rubén, 1978-, Fernández-Fernández, José Manuel, 1967-, García Ojalvo, Jordi, Gursoy, Attila, Keskin, Ozlem, Oliva Miguel, Baldomero, Posas Garriga, Francesc, Nadal Clanchet, Eulàlia de, Muñoz López, Francisco José, 1964-
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55433
Acceso en línea:http://hdl.handle.net/10230/55433
http://dx.doi.org/10.3390/ijms24021278
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
SOCE
SURF4
Amyloid beta-peptide
Calcium
Genome-wide screening
Descripción
Sumario: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.

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