The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.

Rickie Patani,Benjamin E. Clarke,Jasmine Harley

doi:10.3390/antiox10040552

Abstract

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

Highlights

RNA binding proteins (RBPs) represent a family of >1300 proteins that control all aspects of a RNA life cycle, including regulating transcription, processing, localisation, function and decay [1,2]
Mutations in genes implicated in amyotrophic lateral sclerosis (ALS) encode proteins with diverse cellular functions with some convergence, on RBPs including: TAR DNA-binding protein (TARDBP), fused in sarcoma (FUS), TATA-Box Binding Protein Associated Factor 15 (TAF15), EWS RNA Binding Protein 1 (EWSR1), heterogeneous nuclear ribonucleoprotein
Paraspeckles have been hypothesised to have a role in ALS pathology, with ALS-linked RBPs, TDP-43, FUS and SFPQ identified as components of paraspeckles

Summary

Introduction

RNA binding proteins (RBPs) represent a family of >1300 proteins that control all aspects of a RNA life cycle, including regulating transcription, processing, localisation, function and decay [1,2]. This carefully controlled interaction allows a diligent regulation of gene expression. A genetic basis for disease is not restricted to fALS, as mutations in genes found in fALS cases have been identified in up to 25% of apparently sALS cases, which share many neuropathological features [8]. Antioxidants 2021, 10, 552 mechanisms of disease arising from glia are thought to contribute to motor neuron death in ALS. We review the dysfunction of RBPs and their interplay with oxidative stress and mitochondrial dysfunction in ALS, as well as highlight potential therapeutic strategies targeting these pathways

Mechanisms of RNA Binding Protein Dysfunction in ALS

Localisation

Aggregation

Aberrant Granule Dynamics

Post Translational Modifications

Deregulated RNA Metabolism

RNA Binding Proteins and Oxidative Stress in ALS

RNA Binding Proteins and Mitochondrial Dysfunction in ALS

Findings

Conclusions