TDP-43 autoregulation: implications for disease

TDP-43 is a nuclear protein that has been shown to play a central role in RNA metabolism. In recent years, this protein has become very important in the study of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration (FTLD). These diseases share, as common feature, the presence of abnormally aggregated, posttranslationally modified, and mislocalized TDP-43 in the cell cytoplasm of both neurons and glial cells. A major question in TDP-43 research is represented by the investigation of the mechanism(s) that trigger this process and its potential consequences. Regarding the first issue, it is likely that relative protein expression levels might play an important role as has been demonstrated for many protein aggregation processes. In fact, the eventual misregulation of TDP-43 expression leading to enhanced protein production might well correlate with enhanced aggregation, and thus results in increasingly harmful gain- or loss-of-function effects on cellular metabolism. For this reason, it is important to determine the mechanisms that act to regulate TDP-43 levels within the cell. In normal conditions, it is now clear that TDP-43 can modulate its own protein levels through a negative feedback loop triggered by binding to its own RNA in the 3'UTR region leading to mRNA degradation. This work discusses how an eventual disruption of this mechanism might affect TDP-43 pathology, focusing in particular on its association with stress granules and intrinsic aggregation properties.