Contribution of tRNA fragments in the ETiopathogenesis of Huntington's Disease (tR-GET HD)

Informazioni relative al progetto

tR-GET HD

ID dell’accordo di sovvenzione: 101066416

DOI

10.3030/101066416

Progetto chiuso

Data della firma CE 11 Agosto 2022

Data di avvio 15 Ottobre 2022

Data di completamento 14 Marzo 2025

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 188 121,81

Coordinato da

UNIVERSITAT DE BARCELONA
Spain

Periodic Reporting for period 1 - tR-GET HD (Contribution of tRNA fragments in the ETiopathogenesis of Huntington's Disease (tR-GET HD))

Periodo di rendicontazione: 2022-10-15 al 2025-03-14

Sintesi del contesto e degli obiettivi generali del progetto

Huntington’s disease (HD) is a rare but devastating inherited brain disorder that causes progressive movement, cognitive, and psychiatric symptoms. Despite decades of research, there is still no cure. It is known that HD results from a genetic mutation leading to the production of an abnormal form of a protein called huntingtin, but the precise molecular mechanisms driving these events remain unclear.
This project explores how small RNAs and other pathogenic processes might influence the development of HD. Recent discoveries suggest that these molecules and cellular responses could be linked to HD-related neurotoxicity. By investigating their roles in disease progression, the research aims to uncover new molecular mechanisms that could be targeted for therapy.
The work brings together complementary expertise in RNA biology, brain toxicity, and neurodegenerative disease models. Using a range of experimental and computational approaches, the project seeks to identify early changes in HD at the molecular level and evaluate potential strategies to counteract them.
Beyond advancing scientific understanding, the project will strengthen collaborations between leading European neuroscientists and support the researcher’s growth as an independent investigator in neurodegenerative disease research. The ultimate goal is to contribute to the discovery of new, RNA-based therapeutic approaches that may one day benefit people living with Huntington’s disease.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

This project explored how certain small RNAs called tRNA-derived fragments (tRFs) may contribute to the development of HD.
Using advanced sequencing and molecular biology techniques, the project identified specific tRFs that are consistently increased in the brains of people with HD. Interestingly, these changes were not seen in mouse models of the disease, showing that some molecular mechanisms driving HD are unique to humans.
Further experiments revealed that these human tRFs can activate immune responses in brain cells. They trigger the production of inflammatory molecules by engaging cellular sensors that detect foreign or damaged RNA, similar to those used by the immune system to fight infections. This finding suggests that tRFs may contribute to the inflammation observed in HD brains, which can worsen neuronal damage.
The project also showed that these effects occur independently of mutant huntingtin protein, the main hallmark of HD, highlighting a new mechanism of disease. The results together reveal that small RNAs, once thought to have minor roles, may be important drivers of inflammation and disease progression in HD.
These discoveries represent a major scientific advance and could help identify new targets for RNA-based therapies in neurodegenerative diseases. A scientific article reporting these findings is in preparation, and the researchers continue to work to expand these findings.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The project generated new knowledge that goes beyond the current scientific understanding of how tRFs contribute to HD. Until now, the involvement of these small RNA molecules in HD or other neurodegenerative diseases had not been well understood.
The results showed that certain tRFs are increased in human HD brains and can activate immune-related pathways, suggesting that they may contribute to the inflammation commonly seen in the disease. These observations open new perspectives on the causes of brain inflammation in HD and possibly other neurological disorders.
These findings have important potential for the development of new treatments. By targeting the molecules or pathways identified in this work, future therapies could aim to reduce harmful inflammation and protect brain cells. This research also provides a valuable dataset and experimental framework for other scientists studying RNA-based mechanisms in disease.
Further work is now focused on confirming these results in larger sample sets and testing possible ways to block the harmful effects of tRFs. These next steps will help translate the project’s discoveries into innovative approaches for treating neurodegenerative diseases.