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

19 Scopus citations

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

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

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    Wang, Z. F., Ursu, A., Childs-Disney, J. L., Guertler, R., Yang, W. Y., Bernat, V., Rzuczek, S. G., Fuerst, R., Zhang, Y., Gendron, T. D., Yildirim, I., Dwyer, B. G., Rice, J. E., Petrucelli, L., & Disney, M. D. (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, 26(2), 179-190.e12. https://doi.org/10.1016/j.chembiol.2018.10.018