20.500.12556/RUL-164445 Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA 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. genetic mutation aminoacylation amyotrophic lateral sclerosis frontotemporal dementia dementia motor neuron disease genetska mutacija aminoacilacija amiotrofična lateralna skleroza frontotemporalna demenca true false true Angleški jezik Slovenski jezik Članek v reviji 2024-10-25 10:19:34 2024-10-25 10:19:38 2024-11-22 14:54:22 0000-00-00 00:00:00 2023 0 0 15 str. Vol. 14, art. 5764 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 575 2041-1723 10.1038/s41467-023-41511-3 166968323 s41467-023-41511-3_(1).pdf s41467-023-41511-3_(1).pdf 1 BB593861989CD2CF52DC0D6C6318FBCF 195408aafd667e9a3c50426bce3d50939bbb629f58147be97f8a5a00cfbcaa29 1c358d6f-92aa-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=194846 https://www.nature.com/articles/s41467-023-41511-3 0 93f49ac4-92a9-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=194845 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0