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

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

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.

• Jezik: Angleški jezik
• Ključne besede: genetic mutation, aminoacylation, amyotrophic lateral sclerosis, frontotemporal dementia, dementia, motor neuron disease
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: 15 str.
• Številčenje: Vol. 14, art. 5764
• PID: 20.500.12556/RUL-164445
• UDK: 575
• ISSN pri članku: 2041-1723
• DOI: 10.1038/s41467-023-41511-3
• COBISS.SI-ID: 166968323
• Datum objave v RUL: 25.10.2024

Gradivo je del revije

• Naslov: Nature communications
• Skrajšan naslov: Nat. commun.
• Založnik: Springer Nature
• ISSN: 2041-1723
• COBISS.SI-ID: 2315876

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: genetska mutacija, aminoacilacija, amiotrofična lateralna skleroza, frontotemporalna demenca