Phase to Phase with TDP-43

TDP-43 is a dimeric nuclear protein that plays a central role in RNA metabolism. In recent years, this protein has become a focal point of research in the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, as pathognomonic inclusions within affected neurons contain post-translationally modified TDP-43. A key question in TDP-43 research involves determining the mechanisms and triggers that cause TDP-43 to form pathological aggregates. This review gives a brief overview of the physiological and pathological roles of TDP-43 and focuses on the structural features of its protein domains and how they may contribute to normal protein function and to disease. A special emphasis is placed on the C-terminal prion-like region thought to be implicated in pathology, as it is where nearly all ALS/FTD-associated mutations reside. Recent structural studies of this domain revealed its crucial role in the formation of phase-separated liquid droplets through a partially populated α-helix. ...