Roles for RNA-binding proteins in development and disease

Abstract

RNA-binding protein activities are highly regulated through protein levels, intracellular localization, and post-translation modifications. During development, mRNA processing of specific gene sets is regulated through manipulation of functional RNA-binding protein activities. The impact of altered RNA-binding protein activities also affects human diseases in which there are either a gain-of-function or loss-of-function causes pathogenesis. We will discuss RNA-binding proteins and their normal developmental RNA metabolism and contrast how their function is disrupted in disease. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.

Keywords: Development; Neurodegenerative disease; Protein aggregate; Protein mis-regulation; RNA processing; RNA-binding protein.

Fig. 1

Protein levels and subcellular localization of RBPs during development and disease. (A) CELF1 (blue) is regulated by phosphorylation and microRNAs while MBNL1 (red) localization changes during development. In DM, the presence of DMPK expanded CUG-repeat (green) leads to hyper-phosphorylation and stability of CELF1 to increase CELF1 activity, and MBNL1 activity is loss by sequestration by the RNA foci. (B) Normally, TDP-43 (purple) and FUS (orange) are predominantly nuclear proteins that have reduced protein levels during development. Due to mutations (*) in TDP-43 and FUS, TDP-43 and FUS proteins aggregate in the cytoplasm causing a loss of function of TDP-43 and gain of function of FUS.