Small Molecule Targeting TDP-43's RNA Recognition Motifs Reduces Locomotor Defects in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

Liberty François-Moutal, Razaz Felemban, David D. Scott, Melissa R. Sayegh, Victor G. Miranda, Samantha Perez-Miller, Rajesh Khanna, Vijay Gokhale, Daniela C. Zarnescu, May Khanna

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4 Scopus citations


RNA dysregulation likely contributes to disease pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. A pathological form of the transactive response (TAR) DNA binding protein (TDP-43) binds to RNA in stress granules and forms membraneless, amyloid-like TDP-43 aggregates in the cytoplasm of ALS motor neurons. In this study, we hypothesized that by targeting the RNA recognition motif (RRM) domains of TDP-43 that confer a pathogenic interaction between TDP-43 and RNA, motor neuron toxicity could be reduced. In silico docking of 50000 compounds to the RRM domains of TDP-43 identified a small molecule (rTRD01) that (i) bound to TDP-43's RRM1 and RRM2 domains, (ii) partially disrupted TDP-43's interaction with the hexanucleotide RNA repeat of the disease-linked c9orf72 gene, but not with (UG)6 canonical binding sequence of TDP-43, and (iii) improved larval turning, an assay measuring neuromuscular coordination and strength, in an ALS fly model based on the overexpression of mutant TDP-43. Our findings provide an instructive example of a chemical biology approach pivoted to discover small molecules targeting RNA-protein interactions in neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)2006-2013
Number of pages8
JournalACS Chemical Biology
Issue number9
StatePublished - Sep 20 2019


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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