The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS

Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72‐derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient‐derived cells. Cells expressing toxic poly‐GR or poly‐PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine‐rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine‐rich DPR‐mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72‐FTLD/ALS pathologies in a vicious cycle.