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

Mirjana Malnar Črnigoj, Urša Čerček, Xiaoke Yin, Manh Tin Ho, Barbka Repic Lampret, Manuela Neumann, Andreas Hermann, Guy Rouleau, Beat Suter, Manuel Mayr and Boris Rogelj ()
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Mirjana Malnar Črnigoj: Jožef Stefan Institute
Urša Čerček: Jožef Stefan Institute
Xiaoke Yin: King’s College London
Manh Tin Ho: University of Bern
Barbka Repic Lampret: University Children’s Hospital, University Medical Centre Ljubljana
Manuela Neumann: German Center for Neurodegenerative Diseases
Andreas Hermann: University Medical Center Rostock, University of Rostock
Guy Rouleau: McGill University
Beat Suter: University of Bern
Manuel Mayr: King’s College London
Boris Rogelj: Jožef Stefan Institute

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 tRNAPhe by FARS is inhibited by antisense RNA, leading to decreased levels of charged tRNAPhe. 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.

Date: 2023
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DOI: 10.1038/s41467-023-41511-3

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