Abstract
The hexanucleotide repeat expansion GGGGCC [r(G4C2)exp] within intron 1 of C9orf72 causes genetically defined amyotrophic lateral sclerosis and frontotemporal dementia, collectively named c9ALS/FTD., the repeat expansion causes neurodegeneration via deleterious phenotypes stemming from r(G4C2)exp RNA gain- and loss-of-function mechanisms. The r(G4C2)exp RNA folds into both a hairpin structure with repeating 1 × 1 nucleotide GG internal loops and a G-quadruplex structure. Here, we report the identification of a small molecule (CB253) that selectively binds the hairpin form of r(G4C2)exp. Interestingly, the small molecule binds to a previously unobserved conformation in which the RNA forms 2 × 2 nucleotide GG internal loops, as revealed by a series of binding and structural studies. NMR and molecular dynamics simulations suggest that the r(G4C2)exp hairpin interconverts between 1 × 1 and 2 × 2 internal loops through the process of strand slippage. We provide experimental evidence that CB253 binding indeed shifts the equilibrium toward the 2 × 2 GG internal loop conformation, inhibiting mechanisms that drive c9ALS/FTD pathobiology, such as repeat-associated non-ATG translation formation of stress granules and defective nucleocytoplasmic transport in various cellular models of c9ALS/FTD.
Original language | English (US) |
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Pages (from-to) | 4076-4089 |
Number of pages | 14 |
Journal | ACS Chemical Neuroscience |
Volume | 12 |
Issue number | 21 |
DOIs | |
State | Published - Nov 3 2021 |
Keywords
- NMR spectroscopy
- RNA
- amyotrophic lateral sclerosis
- bistable RNA
- frontotemporal dementia
- microsatellite disorders
- quinazoline
- repeat associate non-ATG (RAN) translation
- repeat expansion
- small molecules
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Cognitive Neuroscience
- Cell Biology