Invited Review: Decoding the pathophysiological mechanisms that underlieRNAdysregulation in neurodegenerative disorders: a review of the current state of the art

Abstract

Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins – and how these lead to neurodegeneration – remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression.

Nuclear accumulation of mRNAs underlies G4C2 repeat-induced translational repression in a cellular model of C9orf72 ALS

“…The presence of C9orf72 RNA inclusions in tissues from ALS or frontotemporal dementia (FTD) patients, as well as the formation of similar inclusions in cellular systems expressing the repeats, including iPSC-derived motor neurons, provided an early support for the hypothesis that sequestration of RNA-binding proteins by C9orf72 repeat might have a role in disease pathogenesis (Walsh et al, 2015). Evidence from histopathological analysis of RNA foci in tissues from ALS and/or FTD patients has shown a positive correlation between the number of repeat-containing foci and disease presentation or severity (Cooper-Knock et al, 2014;Mizielinska et al, 2013), further indicating that accumulation of C9orf72-derived G4C2 RNA repeats are primary involved in the neurodegenerative process.…”

“…During the past years, the discovery of mutations in the FUS (also known as TLS), TARDBP and C9orf72 genes led to the concept that alterations in RNA metabolism are a major determinant of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), similar to what occurs in other neurodegenerative diseases (Walsh et al, 2015). Alterations in alternative splicing have been suggested to cause the disease, but other steps of posttranscriptional gene regulation could be equally involved (Achsel et al, 2013).…”

Body Mass Index and Amyotrophic Lateral Sclerosis: A Study of US Military Veterans

“…Interestingly, mutations affecting TDP-43 and FUS are uncommon in patients with ALS and co-occurring frontotemporal dementia that have higher BMI compared with patients without cognitive symptoms (33,34). The most commonly mutated gene in ALS known to date is chromosome 9 open reading frame 72 (C9ORF72), which encodes a protein of still uncharacterized function (35). Nevertheless, C9ORF72 repeat expansions in a mouse model were associated with TDP-43 pathology, decreased body weight, and hyperactivity (36).…”

Current developments in gene therapy for amyotrophic lateral sclerosis

“…There is also increasing evidence for dysregulation of miRNAs in this disease [77]. In 2013 it was reported that endogenous miRNA-155 is significantly upregulated in the spinal cord tissue of both ALS rodent models and human ALS patients [78,79]. In this study, specific ASOs designed to decrease the levels of miRNA-155 in SOD1-G93A mice prolonged survival in this murine model in comparison to scrambled control antimiRNA [78].…”