Pathogenic changes to TAR
DNA-binding protein 43 (TDP-43) leading to alteration of its homeostasis are a common feature shared by several progressive
neurodegenerative diseases for which there is no effective
therapy. Here, we developed Drosophila lines expressing either wild type TDP-43 (WT) or that carrying an
Amyotrophic Lateral Sclerosis /
Frontotemporal Lobar Degeneration-associating G384C mutation that recapitulate several aspects of the TDP-43 pathology. To identify potential
therapeutics for TDP-43-related diseases, we implemented a
drug repurposing strategy that involved three consecutive steps. Firstly, we evaluated the improvement of eclosion rate, followed by the assessment of locomotive functions at early and late developmental stages. Through this approach, we successfully identified
fingolimod, as a promising candidate for modulating TDP-43 toxicity.
Fingolimod exhibited several beneficial effects in both WT and mutant models of TDP-43 pathology, including post-transcriptional reduction of TDP-43 levels, rescue of pupal lethality, and improvement of locomotor dysfunctions. These findings provide compelling evidence for the therapeutic potential of
fingolimod in addressing TDP-43 pathology, thereby strengthening the rationale for further investigation and consideration of clinical trials. Furthermore, our study demonstrates the utility of our Drosophila-based screening pipeline in identifying novel
therapeutics for TDP-43-related diseases. These findings encourage further scale-up screening endeavors using this platform to discover additional compounds with therapeutic potential for TDP-43 pathology.