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Abstract

A repeat expansion in C90RF72 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 it adopts a hairpin structure in equilibrium with a quadruplex structure, Using this model, bioactive small molecules targeting r(GGGGCC)_exp were designed arid found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)₆₆ and neurons trans-differentiated 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/ALS therapeutic, and suggest c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)_exp.

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