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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).
- Source :
-
ACS chemical biology [ACS Chem Biol] 2019 Sep 20; Vol. 14 (9), pp. 2006-2013. Date of Electronic Publication: 2019 Aug 27. - Publication Year :
- 2019
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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) <subscript>6</subscript> 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.
- Subjects :
- Animals
Base Sequence
Binding Sites
DNA-Binding Proteins chemistry
Drosophila Proteins chemistry
Drosophila melanogaster chemistry
Drosophila melanogaster drug effects
Locomotion drug effects
Molecular Docking Simulation
Neuroprotective Agents metabolism
Piperidines metabolism
Protein Domains drug effects
Pyrazines metabolism
RNA metabolism
Small Molecule Libraries metabolism
Amyotrophic Lateral Sclerosis drug therapy
DNA-Binding Proteins metabolism
Drosophila Proteins metabolism
Neuroprotective Agents therapeutic use
Piperidines therapeutic use
Protein Binding drug effects
Pyrazines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 14
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 31241884
- Full Text :
- https://doi.org/10.1021/acschembio.9b00481