The Hairpin Form of r(G 4 C 2 ) exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules

Zi Fu Wang, Andrei Ursu, Jessica L. Childs-Disney, Rea Guertler, Wang Yong Yang, Viachaslau Bernat, Suzanne G. Rzuczek, Rita Fuerst, Yongjie Zhang, Tania D Gendron, Ilyas Yildirim, Brendan G. Dwyer, Joseph E. Rice, Leonard Petrucelli, Matthew D. Disney

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G 4 C 2 repeat [(G 4 C 2 ) exp ] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(G 4 C 2 ) 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(G 4 C 2 ) exp , prevented sequestration of an RBP, and inhibited RAN translation. Indeed, biophysical characterization showed that 4 selectively bound the hairpin form of r(G 4 C 2 ) exp , and nuclear magnetic resonance spectroscopy studies and molecular dynamics simulations defined this molecular recognition event. Cellular imaging revealed that 4 localized to r(G 4 C 2 ) exp cytoplasmic foci, the putative sites of RAN translation. Collectively, these studies highlight that the hairpin structure of r(G 4 C 2 ) exp is a therapeutically relevant target and small molecules that bind it can ameliorate c9ALS/FTD-associated toxicity. The most common cause of ALS is an expanded RNA repeat [r(G 4 C 2 ) exp ] that folds into two forms in vitro, a G-quadruplex and a hairpin. Wang et al. show that the hairpin form is present in cells, undergoes aberrant translation that causes toxicity, and thus is a target for therapeutic development.

Original languageEnglish (US)
Pages (from-to)179-190.e12
JournalCell Chemical Biology
Volume26
Issue number2
DOIs
StatePublished - Feb 21 2019

Fingerprint

Frontotemporal Dementia
RNA-Binding Proteins
Toxicity
RNA
G-Quadruplexes
Molecules
Dipeptides
Poisons
Amyotrophic Lateral Sclerosis
Molecular Dynamics Simulation
Molecular recognition
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance spectroscopy
Molecular dynamics
Assays
Imaging techniques
Computer simulation
Frontotemporal Dementia With Motor Neuron Disease
In Vitro Techniques
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

The Hairpin Form of r(G 4 C 2 ) exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules . / Wang, Zi Fu; Ursu, Andrei; Childs-Disney, Jessica L.; Guertler, Rea; Yang, Wang Yong; Bernat, Viachaslau; Rzuczek, Suzanne G.; Fuerst, Rita; Zhang, Yongjie; Gendron, Tania D; Yildirim, Ilyas; Dwyer, Brendan G.; Rice, Joseph E.; Petrucelli, Leonard; Disney, Matthew D.

In: Cell Chemical Biology, Vol. 26, No. 2, 21.02.2019, p. 179-190.e12.

Research output: Contribution to journalArticle

Wang, ZF, Ursu, A, Childs-Disney, JL, Guertler, R, Yang, WY, Bernat, V, Rzuczek, SG, Fuerst, R, Zhang, Y, Gendron, TD, Yildirim, I, Dwyer, BG, Rice, JE, Petrucelli, L & Disney, MD 2019, ' The Hairpin Form of r(G 4 C 2 ) exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules ', Cell Chemical Biology, vol. 26, no. 2, pp. 179-190.e12. https://doi.org/10.1016/j.chembiol.2018.10.018
Wang, Zi Fu ; Ursu, Andrei ; Childs-Disney, Jessica L. ; Guertler, Rea ; Yang, Wang Yong ; Bernat, Viachaslau ; Rzuczek, Suzanne G. ; Fuerst, Rita ; Zhang, Yongjie ; Gendron, Tania D ; Yildirim, Ilyas ; Dwyer, Brendan G. ; Rice, Joseph E. ; Petrucelli, Leonard ; Disney, Matthew D. / The Hairpin Form of r(G 4 C 2 ) exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules In: Cell Chemical Biology. 2019 ; Vol. 26, No. 2. pp. 179-190.e12.
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abstract = "The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G 4 C 2 repeat [(G 4 C 2 ) exp ] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(G 4 C 2 ) 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(G 4 C 2 ) exp , prevented sequestration of an RBP, and inhibited RAN translation. Indeed, biophysical characterization showed that 4 selectively bound the hairpin form of r(G 4 C 2 ) exp , and nuclear magnetic resonance spectroscopy studies and molecular dynamics simulations defined this molecular recognition event. Cellular imaging revealed that 4 localized to r(G 4 C 2 ) exp cytoplasmic foci, the putative sites of RAN translation. Collectively, these studies highlight that the hairpin structure of r(G 4 C 2 ) exp is a therapeutically relevant target and small molecules that bind it can ameliorate c9ALS/FTD-associated toxicity. The most common cause of ALS is an expanded RNA repeat [r(G 4 C 2 ) exp ] that folds into two forms in vitro, a G-quadruplex and a hairpin. Wang et al. show that the hairpin form is present in cells, undergoes aberrant translation that causes toxicity, and thus is a target for therapeutic development.",
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AU - Guertler, Rea

AU - Yang, Wang Yong

AU - Bernat, Viachaslau

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