Expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.

Expression of an expanded (G4C2)30+ repeat found in C9orf72 is the most prominent mutation in familial FTD and ALS. An unbiased RNAi-based, large-scale screen in (G4C2)49-expressing Drosophila identified the CDC73/PAF1 complex (PAF1C) as a novel suppressor of (G4C2)49-toxicity. Downregulation of PAF1C, an activator of elongating RNAPII, caused suppression by reducing (G4C2)49-RNA levels. Remarkably, only PAF1C components Paf1 and Leo1 were selective for transcription of a long repeat expansion; transcript levels produced from shorter and longer repeat-containing transgenes were similarly affected by other components and Spt4, a previously identified transcriptional regulator of G4C2-repeats. Congruent with our fly data, PAF1 and LEO1 were upregulated in the frontal cortex of C9+ FTD patients and their expression correlated to expression of repeat-containing C9orf72. Surprisingly, this affect was specific to C9+ FTD versus C9+ ALS. This is the first evidence that PAF1C is playing a role in C9orf72-associated FTD. Further, PAF1C may affect other repeat-associated diseases.\n\nHIGHLIGHTSO_LI(G4C2)49-toxicity modifier screen highlights suppressors as RNAPII-transcription regulators\nC_LIO_LIFurther insights into repeat mediated transcription by Spt4/DSIF in C9+ FTD/ALS\nC_LIO_LIAddition of PAF1C as an elongation complex important for promoting RNAPII-transcription of G4C2 repeats O_LI(G4C2)30+ transcription is mediated by Leo1 and Paf1 of the Paf1C complex, not by DSIF\nC_LI\nC_LI