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Citation
Goodman, L.D., Prudencio, M., Kramer, N.J., Martinez-Ramirez, L.F., Srinivasan, A.R., Lan, M., Parisi, M.J., Zhu, Y., Chew, J., Cook, C.N., Berson, A., Gitler, A.D., Petrucelli, L., Bonini, N.M. (2019). Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.  Nat. Neurosci. 22(6): 863--874.
FlyBase ID
FBrf0242463
Publication Type
Research paper
Abstract

An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)30+) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+). Through an unbiased large-scale screen of (G4C2)49-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+-derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.

PubMed ID
PubMed Central ID
PMC6535128 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Neurosci.
    Title
    Nature Neuroscience
    Publication Year
    1998-
    ISBN/ISSN
    1097-6256
    Data From Reference