Abstract:
Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized
by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein
aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43)
are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to
form liquid droplets, which may progress to pathological aggregates. In this study, we established the
NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion
of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners.
A screen of pharmacologically active compounds from the LOPAC®1280 library identified auranofin,
chelerythrine and riluzole as dose-dependent inhibitors of TDP-43 self-interaction. Further analysis of
drug action of the gold-containing thioredoxin reductase inhibitor auranofin revealed a redistribution
from insoluble TDP-43 protein pool to PBS-soluble protein pool in N2a cells. In addition, auranofin
treatment diminished reduced glutathione as a sign for oxidative modulation.
