Malnar Črnigoj, Mirjana; Čerček, Urša; Yin, Xiaoke; Ho, Manh Tin; Repic Lampret, Barbka; Neumann, Manuela; Hermann, Andreas; Rouleau, Guy; Suter, Beat; Mayr, Manuel; Rogelj, Boris (2023). Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA. Nature communications, 14(1), p. 5764. 10.1038/s41467-023-41511-3
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
08 Faculty of Science > Department of Biology > Institute of Cell Biology |
UniBE Contributor: |
Ho, Manh Tin, Suter, Beat (A) |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
2041-1723 |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
18 Sep 2023 11:24 |
Last Modified: |
29 Oct 2023 02:23 |
Publisher DOI: |
10.1038/s41467-023-41511-3 |
PubMed ID: |
37717009 |
BORIS DOI: |
10.48350/186360 |
URI: |
https://boris.unibe.ch/id/eprint/186360 |
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