Introduction: TAR DNA-binding protein-43 (TDP-43) is a ubiquitously expressed RNA-binding protein belonging to the hnRNP family of nuclear proteins. In human disease, its aberrant aggregation in brains has been shown to play a causative role in several neurodegenerative diseases, especially ALS and FTLD.
Areas covered: In this work, we have highlighted what could be the most promising avenues that could be exploited in a profitable manner to modulate TDP-43 pathology. These range from its protein-protein interactions, RNA-protein interactions and its aberrant aggregation process. Recently published articles on these subjects have been reviewed in the writing up of this manuscript.
Expert opinion: Targeting aberrant TDP-43 aggregation in neurodegenerative diseases should be considered both a challenge and an opportunity. The challenge is represented by the central role played by TDP-43 in the general cellular and developmental processes of higher proteins. This characteristic makes it difficult to target this protein in a generalized manner. In addition, and mostly because of this reason, we still lack reliable disease model systems that can reproduce most, if not all, characteristics of the human disease. Nonetheless, recent research is finally starting to provide potential therapeutic targets based on new findings that regard TDP-43 biology and functions.
Keywords: RNA metabolism; TAR DNA-binding protein-43; amyotrophic lateral sclerosis; frontotemporal dementia; hnRNP; protein aggregation.