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

Nucleotide repeat expansions in theC9orf72gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeatRNAaccumulates withinRNAfoci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeatRNAaccumulation, however, remains unclear. TheRNAexosome complex is a multimeric ribonuclease involved in degradation of defectiveRNA. Here, we uncover theRNAexosome as a major degradation complex for pathogenicC9orf72-derived repeatRNA. Knockdown ofEXOSC10, the catalytic subunit of the complex, enhanced repeatRNAandDPRprotein expression levels.RNAdegradation assays confirmed thatEXOSC10 can degrade both sense and antisense repeats. Furthermore,EXOSC10 reduction increasedRNAfoci and repeat transcripts in patient-derived cells. Cells expressing toxic poly-GRor poly-PRproteins accumulate a subset of small nucleolarRNAprecursors, which are physiological substrates ofEXOSC10, as well as excessive repeatRNA, indicating that arginine-richDPRproteins impair the intrinsic activity ofEXOSC10. Collectively, arginine-richDPR-mediated impairment ofEXOSC10 and theRNAexosome complex compromises repeatRNAmetabolism and may thus exacerbateC9orf72-FTLD/ALSpathologies in a vicious cycle.