TDP-43: new aspects of autoregulation mechanisms in RNA binding proteins and their connection with human disease.

The maintenance of correct protein homeostasis ('proteostasis') is an essential activity of mammalian cells to preserve their vital properties and functions. Because of its importance, correct proteostasis is achieved by the cell in several ways and at several levels of each gene expression pathway. In many cases, mRNA-autoregulatory pathways based on a variety of feedback mechanisms have been observed to play a major role in keeping their concentration under control. This is especially true for RNA binding proteins because of their potential ability to bind their own pre-mRNA molecules, and in particular for two subsets of nuclear factors that are commonly referred to as heterogeneous ribonucleoproteins and serine-arginine-rich proteins. Regarding the mechanism, nonsense-mediated RNA degradation triggered by alternative splicing of their own messenger RNA is a very common autoregulation pathway to maintain constant expression levels within the cellular environment. Recently, however, alternative mechanisms other than nonsense-mediated decay have also been described to play a role for other RNA binding protein factors: serine-arginine-rich splicing factor 1 (SRSF1) and transactive response DNA binding protein 43 kDa (TDP-43). The aim of this minireview will be to discuss these old and new autoregulatory processes and their implication in disease development.