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

  • ACS Chem Biol. 2019 Sep 20;14(9):2006-2013. doi: 10.1021/acschembio.9b00481.
Liberty François-Moutal  1  2 ,  Razaz Felemban  1  2  3 ,  David D Scott  1  2 ,  Melissa R Sayegh  4  5  6 ,  Victor G Miranda  1  2 ,  Samantha Perez-Miller  1  2 ,  Rajesh Khanna  1 ,  Vijay Gokhale  7 ,  Daniela C Zarnescu  4  5  6 ,  May Khanna  1  2
Affiliations
  • 1. Department of Pharmacology, College of Medicine , University of Arizona , Tucson , Arizona 85724 , United States.
  • 2. Center for Innovation in Brain Science , University of Arizona , Tucson , Arizona 85721 , United States.
  • 3. King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard , Jeddah , Kingdom of Saudi Arabia.
  • 4. Department of Molecular and Cellular Biology , University of Arizona , Tucson , Arizona 85721 , United States.
  • 5. Department of Neuroscience , University of Arizona , Tucson , Arizona 85721 , United States.
  • 6. Department of Neurology , University of Arizona , Tucson Arizona 85721 , United States.
  • 7. Bio5 Institute , University of Arizona , Tucson , Arizona 85721 , United States.
PMID: 31241884 DOI: 10.1021/acschembio.9b00481
Abstract

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.

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