Cytoplasmic RNA granules, ribostasis, and neurodegeneration.

Abstract

The regulation of translation and decay of messenger RNA (mRNA) is a key mechanism for control of gene expression. During transcription in the nucleus, nascent mRNAs assemble with a set of RNA-binding proteins to form messenger ribonucleoprotein particles (mRNPs). These mRNA-binding proteins regulate transcription, pre-mRNA splicing, mRNA editing, nucleocytoplasmic transport, translation, turnover, and decay. Upon mRNA translation in the cytosol, mRNA-binding proteins are removed for recycling to the nucleus. When mRNA is not engaged in transcription, mRNPs assemble into cytoplasmic structures, including stress granules and processing (P) bodies. Stress granules form in response to several types of cellular stress and transiently store translationally silent mRNAs, associated with mRNA-binding proteins and translation initiation factors. P bodies also contain untranslated mRNAs, as well as translational repressors and components of the mRNA decay machinery and microRNA silencing pathway. Neurons also contain cytoplasmic mRNP transport granules that deliver silenced mRNA to specific cell compartments for local translation at active synapses. A conserved group of mRNA-binding proteins present in cytoplasmic mRNP granules regulate several steps of mRNA processing. These include Staufen, ataxin-2, fragile X mental retardation protein 1 (FRMP1), transactive response DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma/translocated in sarcoma (FUS/TLS), among others. These and other proteins in mRNP granules harbor prion-like domains that mediate protein–protein interactions that mediate their nucleation and dynamics. In normal conditions, mRNP granules are dynamic structures that exchange mRNA and protein components with each other and eventually dissolve or are cleared by autophagy. Prolonged cell stress or mutations of mRNA-binding proteins lead to accumulation of mRNA-binding proteins in the form of persistent amyloid-like structures in stress granules. This toxic accumulation alters the pool of mRNA-binding proteins, reduces mRNAs available for translation, and sequesters other noncoding RNAs or RNA regulatory factors. Accumulation of stress granules containing TDP-43, FUS/TLS, ataxin-2, or associated proteins is a key feature of several neurodegenerative disorders, including amyotrophic lateral sclerosis, some forms of frontotemporal lobar degeneration, and others. There are several comprehensive reviews on the composition, dynamics, and involvement of stress granules and other mRNP granules in neurologic disease. Only salient concepts are emphasized here.