The Messenger in Huntington’s Disease
News Nov 10, 2016
Huntington’s disease is a neurodegenerative disease that is presently incurable. Scientists around the world are researching its causes and molecular processes in the attempt to find a treatment.
The research just published by a group of scientists from the Centre for Genomic Regulation (CRG) led by Eulàlia Martí, in cooperation with researchers from the University of Barcelona (UB) and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), has brought to light new information on the molecular mechanisms that cause Huntington’s disease, and defines new pathways to therapy discovery. The results of the study are published in the November issue of The Journal of Clinical Investigation. Eulàlia Martí is the lead author, while Laura Rué and Mónica Bañez are its first authors.
Huntington’s disease is caused by the excessive repetition of a nucleotide triplet (CAG) in the Huntingtin gene. The number of CAG repetitions varies from person to person. Healthy individuals can have up to 36 repetitions. Nevertheless, as of 36 repetitions, Huntington’s disease develops. The direct consequence of this excess of repetitions is the synthesis of a mutated protein–different from what would be obtained without the additional CAG repetitions–which has been considered the main cause of the disease for the past 20 years.
“What we have observed in our study is that the mutated fragment acting as a conveyor–the so-called messenger RNA–is key in the pathogenesis,” says Dr. Eulàlia Martí, lead author of the research project, together with Xavier Estivill, and acting group leader of the Genes and Disease laboratory at the Centre for Genomic Regulation. “The research on this disease being done by most groups around the world seeking new therapeutic strategies focuses on trying to prevent expression of the mutated protein. Our work suggests that blocking the activity of messenger RNA (the “conveyor”), would be enough to revert the alterations associated with Huntington’s disease. We hope this will contribute to improving the strategies in place to find a cure,” states the researcher.
Going deeper in molecular mechanisms, enables progress to future applications
This work underscores the importance of rethinking the mechanisms behind illnesses to find new treatments. The work of scientists at the CRG has helped explore the molecular mechanisms that cause the disease. Now, their results will contribute to better delimit research efforts towards a cure.
As opposed to most other research groups, Eulàlia Martí’s team has sought to identify whether the problem resided in the messenger RNA – which would be the copy responsible for manufacturing the protein – or in the resulting protein. Prior work indicated that mRNA produced, in addition to defective protein, other damages. This previous work was the starting point for Martí and her fellow researchers, who have finally demonstrated that mRNA has a key role in the pathogenesis of Huntington’s disease. “The research we have just published points to RNA’s clear role in Huntington’s disease. This information is very important in translational research to take on new treatments,” says the researcher.
Story from the Centre for Genomic Regulation. Please note: The content above may have been edited to ensure it is in keeping with Technology Networks’ style and length guidelines.
Rué, L., Bañez-Coronel, M., Creus-Muncunill, J., Giralt, A., Alcalá-Vida, R., Mentxaka, G., … Martí, E. (2016). Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels. Journal of Clinical Investigation, 126(11), 4319–4330. doi:10.1172/jci83185
As genome editing technologies advance toward clinical therapies, they are raising hopes of a completely new way to treat disease. However, challenges need to be addressed before potential treatments can be widely used in patients. To tackle these challenges, the National Institutes of Health has launched the Somatic Cell Genome Editing program, which has awarded multiple grants including more than $3.6 million to assess the safety of genome editing in human cells and tissues.