An allosteric modulator of RNA binding targeting the N-terminal domain of TDP-43 yields neuroprotective properties

Niloufar Mollasalehi, Liberty Francois-Moutal, David D. Scott, Judith A. Tello, Haley Williams, Brendan Mahoney, Jacob M. Carlson, Yue Dong, Xingli Li, Victor G. Miranda, Vijay Gokhale, Wei Wang, Sami J. Barmada, May Khanna

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2854-2859
Number of pages6
JournalACS Chemical Biology
Volume15
Issue number11
DOIs
StatePublished - Nov 20 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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