| Autor: |
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 |
| Zdroj: |
ACS Chemical Biology; September 2019, Vol. 14 Issue: 9 p2006-2013, 8p |
| Abstrakt: |
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 silicodocking 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 c9orf72gene, but not with (UG)6canonical 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. |
| Databáze: |
Supplemental Index |
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