Aberrant RNA processing events in neurological disorders

Abstract

The importance of aberrant RNA processing in neurodegeneration is becoming increasingly clear; a recent example being the identification of the splicing factor TDP-43 as the major component of inclusions characteristic of a number of neurodegenerative conditions including amyotrophic lateral sclerosis (ALS). Due to the enormous diversity generated by alternative splicing and its importance in the nervous system, it is no surprise that defective alternative splicing in disease has been particularly well documented. However, in addition to splicing, other RNA processing events such as RNA editing, polyadenylation and mRNA stability are also disrupted in some neurological disorders. For instance: the editing efficiency of specific ionotropic receptors is reduced in ALS affecting ion permeability and the function of RNA-processing proteins is affected by their sequestration to trinucleotide repeat expanded mRNAs in several disorders. Due to the extensive coupling between RNA processing events and the multifunctionality of the RNA processing factors that regulate them, it is important to consider RNA processing as a whole. Here we review RNA processing events and their extensive coupling to one another and detail the associations of RNA processing including, but not exclusively, alternative splicing with neurodegeneration.

Introduction

The vast majority of neurological diseases are characterised by the presence of abnormal protein aggregates. These lesions can be in the form of extracellular protein deposits that develop as senile plaques or as intracellular inclusions within the cell bodies, nuclei and processes of neurones. As a result of these defining pathological features, neurological diseases are often thought of as diseases of protein metabolism. However, increasing evidence highlights the importance of defective RNA processing in disorders of the nervous system. For example, the RNA-binding protein TDP-43 is a major component of inclusions characteristic of a number of neurodegenerative conditions including ALS (Arai et al., 2006, Kwong et al., 2008, Neumann et al., 2006). Furthermore, mutations in the TDP-43 gene, as well as in the FUS gene, also encoding an RNA-binding protein, have been identified thus confirming their pathological importance (Kwiatkowski et al., 2009, Lagier-Tourenne & Cleveland, 2009, Sreedharan et al., 2008, Vance et al., 2009).

Eukaryotic pre-messenger (m)RNA undergoes extensive post-transcriptional processing through a series of tightly coupled events such as capping, splicing and polyadenylation which protect the transcript on its journey to the cytoplasm and enhance the initiation of translation. In addition, it is thought that the complexity of the human proteome is brought about through processes such as alternative splicing and RNA editing which alter the coding capacity of a transcript. Whilst aberrant alternative splicing has been well documented in neurological disease (Gallo et al., 2005, Licatalosi & Darnell, 2006), it is evident that other RNA processing events such as RNA editing and polyadenylation are also disrupted in some disorders (Abu-Baker & Rouleau, 2007, Kawahara et al., 2004). The purpose of this review is to briefly review RNA processing and detail aberrations in a variety of these intricately coupled events that are involved in neurological disease.