Familial ALS represents a small percentage of all ALS cases and C9ORF72 is the most common mutated gene in familial ALS.
An interesting study identifies PAF1C, as a transcription complex needed to read the C9ORF72 gene expansion RNA in flies and yeast. PAF1C components were upregulated in brain samples from people with C9ORF72-FTD, and bound to the C9ORF72 promoter. The role of PAF1C in expression of the expanded repeats suggests its human homolog may be a target for mitigating C9ORF72 toxicity. It used is about fruit flies, yeast and human tissues. Indeed fruit flies and yeast even more stranger to human CNS than genetically engineered mice. But it is this study that stroked my interest, because they found a link with human FTD where C9 is implicated.
Lindsey Goodman suggests that a potential route to turning off C9orf72-repeat toxicity may be to avert its transcription in the first place.
Using a genetic screen in fruit flies, the scientists sought genes that temper the toxicity of the GGGGCC hexanucleotide repeat that is found in C9orf72 and that lead to the transcription of the C9ORF72-encoded poly(GR) dipeptide.
They were interested in several components of the PAF1C RNA polymerase III complex, which is especially good at transcribing GC-rich DNA. They identified several PAF1C components as modifiers of C9orf72-associated disease.
Transgenic downregulation of PAF1C components disrupted the transcription of G4C2 RNA in both Drosophila and Saccharomyces cerevisiae and resulted in reduced toxicity in Drosophila. 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 human 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.