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Cell Chem Biol. 2019 Feb 21;26(2):179-190.e12. doi: 10.1016/j.chembiol.2018.10.018. Epub 2018 Nov 29.

The Hairpin Form of r(G4C2)exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules.

Author information

1
Departments of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
2
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
3
Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL 33458, USA.
4
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
5
Departments of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: disney@scripps.edu.

Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat [(G4C2)exp] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(G4C2)exp], which sequesters RNA-binding proteins (RBPs) and undergoes repeat-associated non-ATG (RAN) translation to generate toxic dipeptide repeats. Using in vitro and cell-based assays, we identified a small molecule (4) that selectively bound r(G4C2)exp, prevented sequestration of an RBP, and inhibited RAN translation. Indeed, biophysical characterization showed that 4 selectively bound the hairpin form of r(G4C2)exp, and nuclear magnetic resonance spectroscopy studies and molecular dynamics simulations defined this molecular recognition event. Cellular imaging revealed that 4 localized to r(G4C2)exp cytoplasmic foci, the putative sites of RAN translation. Collectively, these studies highlight that the hairpin structure of r(G4C2)exp is a therapeutically relevant target and small molecules that bind it can ameliorate c9ALS/FTD-associated toxicity.

KEYWORDS:

RNA; RNA folding; amyotrophic lateral sclerosis; c9ALS/FTD; chemical biology; drug design; frontotemporal dementia; nucleic acids; small molecules

PMID:
30503283
PMCID:
PMC6386614
[Available on 2020-02-21]
DOI:
10.1016/j.chembiol.2018.10.018

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