An international study, led from the Molecular Physiology Laboratory of the Department of Medicine and Life Sciences (MELIS) from UPF, has identified new genes that modulate the toxicity of the beta-amyloid protein, responsible for causing Alzheimer’s disease.
Combining molecular biology, genomics and bioinformatics techniques, 238 protective or activating genes against Alzheimer’s have been identified. Among them stands out the Surf4 gene, which is involved in the control of intracellular calcium and, by increasing the toxicity of the beta-amyloid protein, contributes to the disease.
7 million new cases of Alzheimer’s each year
Every year, 10 million new cases of dementia are diagnosed worldwide, of which 7 out of 10 are due to Alzheimer’s disease. This disease develops with age, when beta-amyloid protein (a small protein secreted by neurons) begins to misfold and aggregate within the brain causing a neurotoxic effect. At the moment there is no effective treatment to prevent the aggregation and neurotoxicity of the beta-amyloid protein.
In the study, published in the ‘International Journal of Molecular Sciences’, they have identified, in yeast, 238 genes, similar to those in humans, which regulate Alzheimer’s disease. Of these, 81 increase the toxicity of the beta-amyloid protein and 157 are protective against this cellular toxicity.
Bioinformatics analysis
Through a bioinformatic analysis, it has been seen that most of the 238 identified genes are involved in mitochondrial activity, protein translation and intracellular calcium regulation. In this last process, where a large part of the identified genes are involved, the Surf4 gene stands out, whose protein regulates the entry of calcium into the interior of the cell and has turned out to increase the toxicity of the beta-amyloid protein, contributing to the disease Alzheimer’s.
As explained by the coordinator of the study and director of the chair of the QUAES Foundation (promoted by Cetir Ascires) at the Pompeu Fabra University of Barcelona, Francisco J. Muñoz, Calcium is one of the most important messengers that carry information from the outside to the inside of cells. It is involved in almost all cellular functions. “For this reason, when the Surf4 protein is overexpressed, which prevents calcium entry and aborts calcium-dependent cellular processes, neurons cannot function and become very sensitive to amyloid toxicity,” he detailed.
Surf4 identification
The identification of Surf4 as an accelerator of damage due to beta-amyloid protein toxicity opens the door to identifying new therapeutic targets that regulate amyloid toxicity in Alzheimer’s disease. To identify the genes that regulate Alzheimer’s disease, A collection of 5,154 mutants of the yeast Saccharomyces cerevisiae (which share a great similarity with the human genome) in which the expression of a gene has been deleted has been analysed.
Each of these mutants have been crossed with other yeasts of the same strain that overexpress the human beta-amyloid protein and the viability of these cells has been analyzed over several days. In addition, there has been a text mining analysis to identify other genes related to the regulation of beta-amyloid protein toxicity.
The research has been carried out thanks to the support of the Ministry of Science and Innovation, the State Research Agency, FEDER grants, the Spanish Institute of Health Carlos III, ERANET and the QUAES Foundation through the QUAES-UPF Chair of Biomedicine and Engineering Biomedical.