Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

Zhaoming Su, Yongjie Zhang, Tania F. Gendron, Peter O. Bauer, Jeannie Chew, Wang Yong Yang, Erik Fostvedt, Karen Jansen-West, Veronique V. Belzil, Pamela Desaro, Amelia Johnston, Karen Overstreet, Seok Yoon Oh, Peter K. Todd, James D. Berry, Merit E. Cudkowicz, Bradley F. Boeve, Dennis Dickson, Mary Kay Floeter, Bryan J. TraynorClaudia Morelli, Antonia Ratti, Vincenzo Silani, Rosa Rademakers, Robert H. Brown, Jeffrey D. Rothstein, Kevin B. Boylan, Leonard Petrucelli, Matthew D. Disney

Research output: Contribution to journalArticlepeer-review

205 Scopus citations


A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RANtranslation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers.Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

Original languageEnglish (US)
Pages (from-to)1043-1050
Number of pages8
Issue number5
StatePublished - Sep 3 2014

ASJC Scopus subject areas

  • General Neuroscience


Dive into the research topics of 'Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS'. Together they form a unique fingerprint.

Cite this