New discovery important for researching and treating dementia and ALS

Slovenian researchers, under the leadership of Prof. Dr Boris Rogelj of the Faculty of Chemistry and Chemical Technology of the University of Ljubljana and the Biotechnology Department of the Jožef Stefan Institute, have discovered new mechanisms associated with a mutation in gene C9orf72. The research is important since it sheds further light on the causes of two diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and consequently increases the chances of developing new forms of treatment for these two diseases.

The mutation affects the normal functioning of nerve cells in the brains of patients, which is most likely the result of an unusual creation of aggregated proteins. This prevents their normal functioning. This research presents for the first time the compromised binding of repeat RNA with the protein FARS, which causes a reduction in the attachment of the amino acid phenylalanine to the tRNA molecule, and this disrupts protein synthesis.

The research, which has been carried out in an international collaboration, has led to important insights into the molecular basis of ALS and FTD. The participating researchers have optimised a method for observing RNA binding with proteins across the entire cell, which constitutes an innovation in this field of research.

They have additionally identified how patients show a reduced expression of phenylalanine-rich proteins, which could serve as a diagnostic marker for the rapid determination of the type of disease. Meanwhile the FARS protein appears as a new potential therapeutic target for treating patients with this mutation. The research underlines the need for further studies, and highlights a newly developed methodology that will contribute to our understanding and treatment of these complex diseases.

Joining Prof. Dr Boris Rogelj in the research were the young researchers Urša Čerček and Dr Mirjana Malnar Černigoj, Barbka Repič Lampreht of the Ljubljana University Medical Centre and researchers from Germany, Switzerland, the UK and Canada.

Image: The main findings of the research. C4G2 RNA, which forms as a consequence of a mutation in the gene C9orf72, abnormally binds with the protein FARS, which leads to the reduced incorporation of the amino acid phenylalanine into the tRNA molecule. Consequently this reduces the synthesis of proteins rich in phenylalanine. (Author: Urša Čerček)

You can find the article 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. Jul. 2023, vol. 14, article no. 5764, pp. 1-15, illustr. ISSN 2041-1723 DOI: 10.1038/s41467-023-41511-3.