Summary: A new study reveals a new molecular mechanism for Huntington’s disease.
Source: Centre for Genomic Regulation.
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 in order 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 chorea. “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.
More in-depth studies on these mechanisms are yet to be done. For example, research must explore whether it will be possible to revert the effects of Huntington’s disease in patients, just as researchers have demonstrated in mouse models. It also remains to be seen whether the proposal of the CRG researchers can be used in a preventive way, as the disease does not generally appear until after 40 years of age (in humans). Despite the remaining gaps, the published work makes for a key step in knowledge of the mechanisms of this neurodegenerative disease that, as of today, remains incurable.
Source: Laia Cendros – Centre for Genomic Regulation
Image Source: NeuroscienceNews.com image is credited to CRG.
Original Research: Full open access research for “Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels” by Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M. Teresa Zomeño-Abellán,Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, and Eulàlia Martí in Journal of Clinical Investigation. Published online October 10 2016 doi:10.1172/JCI83185
[cbtabs][cbtab title=”MLA”] Centre for Genomic Regulation “The Messenger in Huntington’s Disease.” NeuroscienceNews. NeuroscienceNews, 8 November 2016.
<https://neurosciencenews.com/cag-huntingtons-genetics-5462/>.[/cbtab][cbtab title=”APA”] Centre for Genomic Regulation (2016, November 8). The Messenger in Huntington’s Disease. NeuroscienceNew. Retrieved November 8, 2016 from https://neurosciencenews.com/cag-huntingtons-genetics-5462/[/cbtab][cbtab title=”Chicago”] Centre for Genomic Regulation “The Messenger in Huntington’s Disease.” https://neurosciencenews.com/cag-huntingtons-genetics-5462/ (accessed November 8, 2016).[/cbtab][/cbtabs]
Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels
Huntington’s disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid–modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.
“Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels” by Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M. Teresa Zomeño-Abellán,Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, and Eulàlia Martí in Journal of Clinical Investigation. Published online October 10 2016 doi:10.1172/JCI83185