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

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.