RNA Dysregulation in Amyotrophic Lateral Sclerosis.

Zoe Butti,Shunmoogum A Patten

doi:10.3389/fgene.2018.00712

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease and is characterized by the degeneration of upper and lower motor neurons. It has become increasingly clear that RNA dysregulation is a key contributor to ALS pathogenesis. The major ALS genes SOD1, TARDBP, FUS, and C9orf72 are involved in aspects of RNA metabolism processes such as mRNA transcription, alternative splicing, RNA transport, mRNA stabilization, and miRNA biogenesis. In this review, we highlight the current understanding of RNA dysregulation in ALS pathogenesis involving these major ALS genes and discuss the potential of therapeutic strategies targeting disease RNAs for treating ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder of motor function
We focus on the four major ALS-associated genes (SOD1, TARDBP, FUSED IN SARCOMA (FUS), and C9orf72) and present how they play critical roles in various RNA pathways
SOD1G93A mice treated with injection of associated virus (AAV) encoding short hairpin RNA (shRNA) against human SUPEROXIDE DISMUTASE-1 (SOD1) mRNA exhibited delayed diseases onset and significantly increased their survival by 23% (Foust et al, 2013)

Summary

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder of motor function. There have been several transcriptome investigations in SOD1 human samples (D’Erchia et al, 2017), motor neuron-like NSC34 cell culture model (Kirby et al, 2005) and transgenic animals including mice (Lincecum et al, 2010; Bandyopadhyay et al, 2013; Sun et al, 2015), rat (Hedlund et al, 2010) and drosophila (Kumimoto et al, 2013) These studies have reported dysregulation of genes involved in pathways related to the neuroinflammatory and immune response, oxidative stress, mitochondria, lipid metabolism, synapse and neurodevelopment (Hedlund et al, 2010; Lincecum et al, 2010; Bandyopadhyay et al, 2013; Kumimoto et al, 2013; Sun et al, 2015; D’Erchia et al, 2017). These studies support the further development of small molecules that selectively bind GGGGCC RNA as a therapeutic strategy for C9orf ALS and FTLD

LIMITATIONS

Findings

CONCLUSION