TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis.

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 efficacious medicine to prevent or to stop disease progression. The discovery of mutations in the TARDBP gene (encoding the nuclear protein known as TDP-43) in both FTLD and ALS patients provided evidence for a link between TDP-43 alterations and neurodegeneration. Our understanding of TDP-43 function has advanced profoundly in the past several years; however, its complete role and the molecular mechanisms that lead to disease are not fully understood. Here we summarize the recent studies of this protein, its relation to neurodegenerative diseases, and the therapeutic strategies for restoring 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 for the discovery of pharmacological agents for the treatment of TDP-43-related diseases.