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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalACS Chemical Biology
DOIs
StateAccepted/In press - Jan 1 2019

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Amyotrophic Lateral Sclerosis
Drosophila
RNA
Defects
Molecules
Motor Neurons
Neurodegenerative diseases
Neurodegenerative Diseases
Neurons
DNA-Binding Proteins
Protein Transport
Amyloid
Diptera
Computer Simulation
Cytoplasm
RNA Recognition Motif
Toxicity
Assays
Genes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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Small Molecule Targeting TDP-43's RNA Recognition Motifs Reduces Locomotor Defects in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS). / François-Moutal, Liberty; Felemban, Razaz; Scott, David D.; Sayegh, Melissa R.; Miranda, Victor G.; Perez-Miller, Samantha; Khanna, Rajesh; Gokhale, Vijay; Zarnescu, Daniela C; Khanna, May.

In: ACS Chemical Biology, 01.01.2019.

Research output: Contribution to journalArticle

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