An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties

  • ACS Chem Biol. 2020 Nov 20;15(11):2854-2859. doi: 10.1021/acschembio.0c00494.
Niloufar Mollasalehi  1  2  3 ,  Liberty Francois-Moutal  1  2 ,  David D Scott  1  2 ,  Judith A Tello  1  2 ,  Haley Williams  1  2 ,  Brendan Mahoney  4 ,  Jacob M Carlson  1  2 ,  Yue Dong  5  6 ,  Xingli Li  7 ,  Victor G Miranda  1  2 ,  Vijay Gokhale  8 ,  Wei Wang  5  6 ,  Sami J Barmada  7 ,  May Khanna  1  2
Affiliations
  • 1. Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
  • 2. Center of Innovation in Brain Science, Tucson, Arizona 85721, United States.
  • 3. Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721-0041, United States.
  • 4. Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, California 90095, United States.
  • 5. Arizona Center for Drug Discovery, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 6. Pharmacology and Toxicology Department, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 7. Department of Neurology, University of Michigan Health System, Ann Arbor, Michigan 48109, United States.
  • 8. Bio5 Institute, University of Arizona, Tucson, Arizona 85721, United States.
PMID: 33044808 DOI: 10.1021/acschembio.0c00494
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.

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