Accumulation of TDP-43 in the cytoplasm of diseased neurons is the pathological hallmark of Frontotemporal Dementia-TDP (FTLD-TDP) and Amyotrophic Lateral Sclerosis (ALS), two diseases that lack of efficacious medicine to prevent or to stop disease progression. The discovery that mutations in the TARDBP gene (coding for the nuclear protein known as TDP-43) in both FTLD and ALS patients provided evidence for a link between TDP-43 alterations and neurodegeneration. The knowledge of TDP-43 function has advanced profoundly in the last years, however its complete role and the molecular mechanisms that lead to disease have yet to be fully understood. Here we summarize the recent studies of this protein, its relation to neurodegenerative diseases and the therapeutic strategies to restore its homeostasis with small molecules. Finally, we briefly discuss the available cellular and animal models that help to shed light on TDP-43 pathology and could serve as tools to discover pharmacological agents for the treatment of TDP-43 related diseases.

Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians.