Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA
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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. Focusing on cytoplasmic interaction of the CCCCGG antisense repeat RNA this study identifies phenylalanine-tRNA synthetase (FARS) subunit alpha (FARSA) as the main interactor. 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 significant decrease in expression of phenylalanine-rich proteins in cellular models and patient tissues. In conclusion, this research 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.
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Suspension Culture
SUBMITTER: Xiaoke Yin
LAB HEAD: Manuel Mayr
PROVIDER: PXD042474 | Pride | 2023-09-18
REPOSITORIES: pride
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