ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells.

Cell Rep
Authors
Keywords
Abstract

Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells. The ability of rG4C2 to promote phase separation is dependent on repeat length and RNA structure because rG4C2 must assume a G-quadruplex conformation to promote granule assembly. We demonstrate a central role for RNA in promoting phase separations and implicate rG4C2 G-quadruplex structures in the pathogenesis of C9-ALS/FTD.

Year of Publication
2017
Journal
Cell Rep
Volume
21
Issue
12
Pages
3573-3584
Date Published
2017 Dec 19
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.11.093
PubMed ID
29262335
PubMed Central ID
PMC5741101
Links
Grant list
R21 NS094918 / NS / NINDS NIH HHS / United States
R01 AI033600 / AI / NIAID NIH HHS / United States
R01 GM111700 / GM / NIGMS NIH HHS / United States
T32 AI007306 / AI / NIAID NIH HHS / United States
R01 CA168872 / CA / NCI NIH HHS / United States