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

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

来源：Neuron, 2014, 83(5): 1043-1050.

DOI：10.1016/j.neuron.2014.07.041

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 a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC) exp were designed and found to significantly inhibit RAN translation 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) c9RANproteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)(exp)-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)(exp).

• 出版日期2014-9-3