A new therapeutic target for the Huntington treatment

Huntington’s disease is caused by a mutation in the Huntington gene (HTT), which appears in adults and is characterized by motor, cognitive and psychological changes. The origin of this disease has been linked to the abnormal function of the mutated protein: mHTT, but recent data have shown the involvement of other molecular mechanisms.

A new study by the University of Barcelona has identified a type of RNA as a possible therapeutic target for treating the disease. These are small RNA molecules, or sRNAs, that do not encode proteins but have important functions in regulating gene expression. According to the study, sRNAs will participate in disease progression, the findings that shed light on designing new specific drugs to block the activity of these intermediary molecules that help researchers understand the information in genes.

The study published in the journal Acta Neuropatology, Based on the participation of two teams from the Institute of Neurosciences at UB, led by lecturers at the Faculty of Medicine and Health Sciences, Eulàlia Martí, who is also a researcher at the Biomedical Research Center (CIBERESP) for epidemiology and public health networks; Esther Pérez-Navarro is also a researcher at the Center for Biomedical Research Networks on Degenerative Neurodegenerative Diseases (CIBERNED), August Pi i Sunyer Institute for Biomedical Research (IDIBELL), Center for Genomic Regulation (CRG) and University Medical Center in Göttingen (Germany).

Innovative technology

The aim of the researchers in the study was to understand the toxic potential of the RNA chain that is being generated in the brains of patients with Huntington’s disease. The researchers note that identifying mechanisms of toxicity is important for understanding how disease progresses and designing appropriate drugs and treatment strategies.

To solve this question, the researchers isolated RNA from the brains of patients with Huntington’s disease and from people without the disease, for use as a comparative model. Next, they administered these molecules into the brains of normal mice and analyzed whether the mice had developed anomalies similar to those found in human disease. “This is the first time that we have used an injection of human RNA in the brain of mice, and this innovative strategy has enabled us to understand the importance of these molecules independently of the protein,” notes Yulia Marty.

The results of this experiment show that rRNA in patients with Huntington’s is sufficient to cause similar pathologies in normal mice, which include “motility and transcriptional changes similar to those observed in human and mouse disease models, and a specific effect on the most damaged neurons type during the course of the disease” Loss of nerve cells and nerve inflammation, “says the researcher.

A new perspective on the role of RNA in disease

These results indicate a new view on the role of different types of tRNA in disease development. So far, researchers have shown that both the mHTT protein and the RNA that it codes for and in which CAG is repeated, contribute to neurotoxicity. However, the toxic effects related to RNAs with CAG replication do not explain some important modifications in the pathology context, for example, specific neurotrophic or transcriptional alterations. These results – the researcher continues – show that different types of rRNA created in the patients’ brains are likely to be involved in the pathogenesis of the disease.

In this sense, the study shows that RNA-derived fragments, tRFs, are the most frequently altered types of RNA in the brain of patients with Huntington’s disease. The study shows that specific tRF can cause neurotoxicity, indicating that tRFS could participate in the adverse effects associated with sRNAs in affected patients. After this study, the main goal is to understand the functional relevance of different classes of RNAs, with a special focus on tRFs that are abundant in affected human brains. “Understanding the dynamics of the expression of toxic groups in brain regions and in disease development is critical to obtaining a complete view of their effect on the pathological process,” highlights Yulia Marty.

Potential biomarkers

Moreover, these molecules could become potential biomarkers of disease, given multiple evidence showing that changes in the expression of RNAs occur before symptoms appear. The authors say that “these changes can be reflected in biological fluids such as plasma, and this fact can give these species a great value as biomarkers.”

Finally, these results may have implications in treating other diseases. “Alterations in the expression of sRNAs were discovered early in many neurodegenerative diseases, and thus, we can find a broader field of study to understand the categories that may contribute to specific aspects related to neurodegeneration and neuritis,” the researcher concludes.


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