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

Author

Listed:
  • Mirjana Malnar Črnigoj

    (Jožef Stefan Institute
    University of Ljubljana)

  • Urša Čerček

    (Jožef Stefan Institute
    University of Ljubljana)

  • 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
    University Hospital of Tübingen)

  • Andreas Hermann

    (University Medical Center Rostock, University of Rostock
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE))

  • Guy Rouleau

    (McGill University
    Montreal Neurological Institute, McGill University)

  • Beat Suter

    (University of Bern)

  • Manuel Mayr

    (King’s College London)

  • Boris Rogelj

    (Jožef Stefan Institute
    University of Ljubljana)

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.

Suggested Citation

  • Mirjana Malnar Črnigoj & Urša Čerček & Xiaoke Yin & Manh Tin Ho & Barbka Repic Lampret & Manuela Neumann & Andreas Hermann & Guy Rouleau & Beat Suter & Manuel Mayr & Boris Rogelj, 2023. "Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41511-3
    DOI: 10.1038/s41467-023-41511-3
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    References listed on IDEAS

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