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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Alzheimer's disease (AD) is linked to misfolded amyloid-beta peptide (Aβ) but lacks effective preventatives.
• Understanding molecular players in Aβ toxicity is crucial for developing new AD treatments.

Purpose of the Study:

• To identify novel genes influencing Aβ toxicity using a genome-wide screen.
• To investigate the role of SURF4 in Aβ-induced neurotoxicity and calcium regulation.

Main Methods:

• Conducted a genome-wide screen in yeast (Saccharomyces cerevisiae) with Aβ1-42 expression.
• Performed interactome and text-mining studies to identify affected cellular functions.
• Utilized human neuroblastoma cells for in vitro analysis of SURF4 function and Aβ1-42 cytotoxicity.

Main Results:

• Identified 81 mammalian orthologue genes enhancing and 157 protecting against Aβ1-42 toxicity.
• Found calcium regulation, protein translation, and mitochondrial activity as key affected cellular functions.
• Demonstrated that SURF4 silencing increases intracellular calcium, while overexpression decreases it; SURF4 silencing reduced Aβ1-42 cell death, and overexpression increased it.

Conclusions:

• SURF4 contributes to Aβ1-42 neurotoxicity by decreasing store-operated calcium entry (SOCE).
• Targeting SURF4 or its regulation of SOCE may offer a novel therapeutic strategy for Alzheimer's disease.