Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA

Malnar, Mirjana (author), Čerček, Urša (author), Yin, Xiaoke (author), Tin Ho, Manh (author), Repič-Lampret, Barbka (author), Neumann, Manuela (author), Hermann, Andreas (author), Rouleau, Guy (author), Suter, Beat (author), Mayr, Manuel (author), Rogelj, Boris (author)

The expanded hexanucleotide GGGGCC repeat mutation in the C9orf72 gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Under one disease mechanism, sense and antisense transcripts of the repeat are predicted to bind various RNA-binding proteins, compromise their function and cause cytotoxicity. Here we identify phenylalanine-tRNA synthetase (FARS) subunit alpha (FARSA) as the main interactor of the CCCCGG antisense repeat RNA in cytosol. The aminoacylation of tRNA$^{Phe}$ by FARS is inhibited by antisense RNA, leading to decreased levels of charged tRNA$^{Phe}$. Remarkably, this is associated with global reduction of phenylalanine incorporation in the proteome and decrease in expression of phenylalanine-rich proteins in cellular models and patient tissues. In conclusion, this study reveals functional inhibition of FARSA in the presence of antisense RNA repeats. Compromised aminoacylation of tRNA could lead to impairments in protein synthesis and further contribute to C9orf72 mutation-associated pathology.

• Language: English
• Keywords: genetic mutation, aminoacylation, amyotrophic lateral sclerosis, frontotemporal dementia, dementia, motor neuron disease
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 15 str.
• Numbering: Vol. 14, art. 5764
• PID: 20.500.12556/RUL-164445
• UDC: 575
• ISSN on article: 2041-1723
• DOI: 10.1038/s41467-023-41511-3
• COBISS.SI-ID: 166968323
• Publication date in RUL: 25.10.2024

Record is a part of a journal

• Title: Nature communications
• Shortened title: Nat. commun.
• Publisher: Springer Nature
• ISSN: 2041-1723
• COBISS.SI-ID: 2315876

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: genetska mutacija, aminoacilacija, amiotrofična lateralna skleroza, frontotemporalna demenca