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Slovenian researchers led by Prof. Dr Boris Rogelj from the Faculty of Chemistry and Chemical Technology University of Ljubljana, and the Department of Biotechnology, Jožef Stefan Institute, have discovered new mechanisms associated with a mutation in the C9orf72 gene. This research is important because it further reveals the causes of two diseases – amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) - and, as a consequence, increases the potential for developing new treatments for these two diseases.

The mutation affects the normal functioning of nerve cells in the brains of patients, most likely due to abnormal protein aggregation. This prevents them from functioning normally. This study is the first to report an abnormal association of RNA repeats with the FARS protein, which causes a reduction in the attachment of the amino acid phenylalanine to the tRNA transfer molecule, thereby interfering with protein production.

The research, carried out in an international collaboration, has led to important insights into the molecular basis of ALS and FTD. The collaborating researchers have optimised a method to observe RNA-protein binding throughout the cell, which represents an innovation in this research field.

In addition, they identified that patients have reduced expression of phenylalanine-rich proteins, which could serve as a diagnostic marker for rapid disease typing. The FARS protein is emerging as a new potential therapeutic target for the treatment of patients with this mutation. The study highlights the need for further research and highlights a newly developed methodology that will contribute to the understanding and treatment of these complex diseases.

In addition to Prof. Dr. Boris Rogelj, the study also involved young researchers Urša Čerček and Dr. Mirjana Malnar Černigoj, Barbka Repič Lampreht from UKC Ljubljana, and researchers from Germany, the UK and Canada.

The full article is available here.

Source: MALNAR, Mirjana, ČERČEK, Urša, YIN, Xiaoke, TIN HO, Manh, REPIČ-LAMPRET, Barbka, NEUMANN, Manuela, HERMANN, Andreas, ROULEAU, Guy, SUTER, Beat, MAYR, Manuel, ROGELJ, Boris. Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA. Nature communications. 2023, vol. 14, article no. 5764, str. 1-15, ilustr. ISSN 2041-1723. DOI: 10.1038/s41467-023-41511-3.