RNA Dysregulation in Amyotrophic Lateral Sclerosis

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.

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

“…RNA sequencing identified alternative splicing changes affecting RNA processing and degradation pathways as an early molecular signature of disease, which worsens with disease progression. Similar to C9orf72 ALS/FTD patients (Butti & Patten, 2018, Prudencio et al, 2017, gene expression changes in neuroinflammatory and neurodegenerative pathways predominate in severely affected end-stage animals. Finally, isogenic sub-lines generated from the single copy C9-500 line with 800 repeats (C9-800) show increased RNA foci and RAN protein aggregates as well as earlier ages of onset and increased disease penetrance.…”

“…RNA dysregulation is thought to play a role in C9orf72 ALS/FTD (Butti & Patten, 2018, Prudencio, Gonzales et al, 2017 but little is known about how the transcriptome is affected early in the course of disease or how these changes progress over time. To look for transcriptomic abnormalities that occur during disease progression, we performed RNA sequencing on frontal cortex samples from ten female C9-500 mice at 20 weeks of age with no overt cage behavior abnormalities (C9+ presymptomatic), four C9+ animals that developed acute rapidly progressive phenotypes (20-22 weeks old) (Acute) and three NT controls.…”

Phenotypic Suppression of ALS/FTD-Associated Neurodegeneration Highlights Mechanisms of Dysfunction

“…Using humanized mice in which ALS/FTDcausing FUS mutations provoke age-dependent progressive motor and cognitive deficits, the inhibition of local translation in sciatic nerves was observed before development of disease and was accompanied by increased axonal accumulation of mutant FUS. This work provided in vivo evidence for local intra-axonal translation in adult mice and uncovered a role of FUS in local protein synthesis, extending its cellular functions beyond its known roles in RNA processing, microRNA biogenesis, and mRNA transport (Butti and Patten, 2018). It also raises the possibility that, like deficits in translation observed in C9orf72 and TDP-43-associated ALS/FTD (Kanekura et al, 2016;Cestra et al, 2017;Balendra and Isaacs, 2018;Lehmkuhl and Zarnescu, 2018), impaired local translation may contribute to, or even cause, the age-dependent neurodegeneration associated with mutations in FUS.…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…Ultimately, ALS is fatal, and the time to death is related to the rate of progression [197,198]. As with other neurodegenerative disorders, neuroin lammation is frequently found in ALS [199]. ALS is characterized by in lammation related to astroglia/microglia, macrophages, and pro-in lammatory peripheral lymphocytes [200].…”