The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS patient brains

An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been
proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate
with proteins, but whether this occurs and contributes to disease is unknown. Here we
show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro
is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then
show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes
compared to those without the expansion, and more frequently colocalize with hnRNP H.
Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target
transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q
aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H
as a significant contributor to neurodegeneration in C9 ALS/FTD. [Read More]

Erin G Conlon, Lei Lu,
Aarti Sharma,Takashi Yamazaki,
Timothy Tang, Neil A Shneider,
James L Manley