Open AccessA Small Molecule Exploits Hidden Structural Features within the RNA Repeat Expansion That Causes c9ALS/FTD and Rescues Pathological Hallmarks
Author(s) -
Andrei Ursu,
Jared T. Baisden,
Jessica A. Bush,
Amirhossein Taghavi,
Sonal Choudhary,
Yongjie Zhang,
Tania F. Gendron,
Leonard Petrucelli,
Ilyas Yildirim,
Matthew D. Disney
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00470
Subject(s) - c9orf72 , trinucleotide repeat expansion , neurodegeneration , rna , frontotemporal dementia , biology , genetics , computational biology , microbiology and biotechnology , gene , medicine , allele , dementia , disease , pathology
The hexanucleotide repeat expansion GGGGCC [r(G 4 C 2 ) 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(G 4 C 2 ) exp RNA gain- and loss-of-function mechanisms. The r(G 4 C 2 ) 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(G 4 C 2 ) 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(G 4 C 2 ) 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.