One step closer to Alzheimer's cure? Scientists find new genes that might help

The 238 genes identified by the team could modulate the toxicity of the protein beta-amyloid. 

One gene out of 238 stood out

The team first analyzed over 5,000 mutants of a yeast called Saccharomyces cerevisiae - which is genetically similar to humans. The cell study of these mutations uncovered 238 genes. A bioinformatic analysis showed that almost all of the genes were involved in mitochondrial activity, protein translation, and intracellular calcium regulation.

The study identified that of the lot, 81 genes increased the toxicity of the beta-amyloid protein, and 157 were protective against cellular toxicity. But one particular gene stood out. Identified as Surf4, the research says that this gene’s protein regulates the entry of calcium inside the cell and also increases the toxicity of the beta-amyloid protein, in turn contributing to Alzheimer’s disease. 

Study’s coordinator, Francisco J. Muñoz further explains: “Calcium is one of the most important messengers that transfer information from the outside to within cells. It is involved in almost all cell functions. Hence, when the Surf4 protein is overexpressed, which decreases calcium entry and aborts the cellular processes dependent on it, neurons cannot function, and they become very sensitive to amyloid toxicity.”

The identification of this gene can help the medical industry’s current understanding of how to treat Alzheimer’s by way of regulating amyloid toxicity. It is imperative that new targets to treat Alzheimer’s are identified due to the high number of patients globally. The number of Alzheimer’s diagnoses is bound to increase, given the increase in life expectancy. 

The research stipulates that further work is needed to throw light on the role of the other proteins found in this study.

The research was supported by the Spanish Ministry of Science and Innovation, the State Research Agency, ERDF grants, the Spanish Institute of Health Carlos III, ERANET, and the QUAES Foundation through the QUAES-UPF Chair of Biomedicine and Biomedical Engineering.

Study 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 SURF4overexpression 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.