Open AccessAn Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties
Author(s) -
Niloufar Mollasalehi,
Liberty FrançoisMoutal,
David D. Scott,
Judith A. Tello,
Haley Williams,
Brendan J. Mahoney,
Jacob M. Carlson,
Yue Dong,
Xingli Li,
Victor G. Miranda,
Vijay Gokhale,
Wei Wang,
Sami J. Barmada,
May Khanna
Publication year - 2020
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.0c00494
Subject(s) - allosteric regulation , rna , rna binding protein , binding domain , microbiology and biotechnology , binding site , neuroprotection , chemistry , amyotrophic lateral sclerosis , riboswitch , biochemistry , plasma protein binding , biophysics , biology , neuroscience , non coding rna , enzyme , medicine , gene , disease , pathology
In this study, we targeted the N-terminal domain (NTD) of transactive response (TAR) DNA binding protein (TDP-43), which is implicated in several neurodegenerative diseases. In silico docking of 50K compounds to the NTD domain of TDP-43 identified a small molecule (nTRD22) that is bound to the N-terminal domain. Interestingly, nTRD22 caused allosteric modulation of the RNA binding domain (RRM) of TDP-43, resulting in decreased binding to RNA in vitro . Moreover, incubation of primary motor neurons with nTRD22 induced a reduction of TDP-43 protein levels, similar to TDP-43 RNA binding-deficient mutants and supporting a disruption of TDP-43 binding to RNA. Finally, nTRD22 mitigated motor impairment in a Drosophila model of amyotrophic lateral sclerosis. Our findings provide an exciting way of allosteric modulation of the RNA-binding region of TDP-43 through the N-terminal domain.