2023-11-18 06:45:42
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control. Scientists have designed a potential therapeutic strategy to combat this pathology that still has no treatment.
The new strategy is based on a molecular trap that prevents one of the most common genetic ALS-causing peptide compounds, the polyGR dipeptide, from causing its toxic effects in the body. The results show that this strategy reduces the death of neurons in patients and in an animal model (vinegar flies) of the disease.
The study is the work of an international team that includes scientists from the University of Barcelona (UB).
The first authors of this research are the experts Juan Alberto Ortega Cano, from the Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBneuro) of the UB, and Ivan Sasselli, from the Center for Materials Physics, dependent on the Council Higher Scientific Research Institute (CSIC) and the University of the Basque Country (UPV/EHU), in Spain. Researchers from the University of Zaragoza (Spain) and the University of the Northwest (United States), among others, have also participated.
One of the most common genetic causes of ALS is the mutation in the C9orf72 gene, since it is found in approximately 33% of patients affected by familial ALS and 5% of those affected by sporadic ALS in Spain. In these patients, dipeptides with a large amount of positive charges are generated that generate highly toxic effects on motor neurons. In the first part of the study, the researchers combined computational and experimental techniques to improve the molecular understanding of these dipeptides and how they produce this pathological process.
Artistic recreation of diseased motor neurons. (Image: Amazings/NCYT)
A toxic junction for neurons
The results showed that the toxicity of these compounds is due in part to their binding to ribosomal RNA (rRNA), a molecule that participates in the process of translation of genetic information and protein synthesis in the cell. «We have seen that these dipeptides, especially those rich in the amino acid arginine (poly-glycine-arginine or poly-GR), bind to a specific region of the rRNA, affecting the biosynthesis of ribosomes (small structures that are responsible for synthesizing proteins. of our body) and the translation of proteins in human motor neurons, causing their death,” explains Professor Juan Alberto Ortega Cano. “In addition,” adds the researcher, “this interaction of poly-GR with rRNA is much stronger than the interaction of poly-GR with other ribosomal proteins that had been previously described in other studies, and explains why these dipeptides have great affinity.” in binding to the ribosomes of cells.
Given these results, the researchers designed an innovative strategy to “trick” the poly-GR dipeptides and reduce their toxicity. They created a trap, a molecule that mimicked the specific rRNA sequence with which poly-GR bind during the pathological process, with the aim of avoiding the neurotoxic effects of this binding. The application of this strategy in neurons derived from patient tissue in vitro and in models of the disease (vinegar flies) in vivo show that it “reduces defects in ribosome biosynthesis in protein translation and toxicity in cells that express poly-GR, as well as death in motor neurons of ALS patients with mutations in the C9orf72 gene,” details the researcher.
Although there is still a lot of research to validate and fully understand how this strategy works, the researchers point out that these promising results reinforce the idea that the use of RNA traps is useful “not only to study RNA-protein interactions, but also to protect neurons from the harmful effects of abnormal proteins that are generated in other neurodegenerative diseases.
The study is titled “CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology.” And it has been published in the academic journal Science Advances. (Source: UB)
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