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, Yong Jie Zhang, Tania F. Gendron, Ilyas Yildirim, Brendan G. Dwyer, Joseph E. Rice, Leonard Petrucelli, Matthew D. Disney

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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
Issue number2
StatePublished - Feb 21 2019


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

ASJC Scopus subject areas

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


Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this