Journal of Molecular Biology
Volume 431, Issue 9, 19 April 2019, Pages 1780-1791
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Review
RNA-Mediated Disease Mechanisms in Neurodegenerative Disorders

https://doi.org/10.1016/j.jmb.2018.12.012Get rights and content

Highlights

  • RNA is involved in virtually all pathways that maintain cellular homeostasis.

  • Dysregulation of RNA levels results in altered protein homeostasis.

  • Abnormal RNA::RNA or RNA–protein interactions lead to functional deficits.

  • Novel toxic RNA species arise from repeat expansions and might contribute to disease.

  • Altered RNA structure leads to changes in translation.

Abstract

RNA is accurately entangled in virtually all pathways that maintain cellular homeostasis. To name but a few, RNA is the “messenger” between DNA encoded information and the resulting proteins. Furthermore, RNAs regulate diverse processes by forming DNA::RNA or RNA::RNA interactions. Finally, RNA itself can be the scaffold for ribonucleoprotein complexes, for example, ribosomes or cellular bodies. Consequently, disruption of any of these processes can lead to disease. This review describes known and emerging RNA-based disease mechanisms like interference with regular splicing, the anomalous appearance of RNA–protein complexes and uncommon RNA species, as well as non-canonical translation. Due to the complexity and entanglement of the above-mentioned pathways, only few drugs are available that target RNA-based disease mechanisms. However, advances in our understanding how RNA is involved in and modulates cellular homeostasis might pave the way to novel treatments.

Introduction

Neurodegenerative diseases become one of the main causes of death due to increased general health and hence an increased life-span. National science academies from the G7 countries identified the “challenges of neurodegenerative disease in an aging population” in 2017. From a purely economic point of view, the associated financial burden due to treatments, care, and others, is predicted to reach only in the United States 1 trillion US$ per year by 2050 [1]. Consequently, there is an immense interest of pharmaceutical companies in these diseases because of the high profit margin.

The heterologous group of neurodegenerative diseases includes the two most common ones, which are Alzheimer's and Parkinson's disease, but also rarer ones like amyotrophic lateral sclerosis (ALS)/frontal lobe dementia (FTD), Huntington's disease (HD) and other microsatellite expansion disorders and prion-based disease. A description of the cause(s) of each disease, symptoms and pathological features is beyond the scope of this review and has been extensively reviewed elsewhere [2]. This review will focus on the fascinating world of RNA and how disease-related alterations in RNA biology contribute to neurodegenerative diseases. At that, important lessons can be learnt from studying other disorders that are caused by RNA-mediated disease mechanisms. First, I highlight the roles of RNA in disease. For example, dysregulated RNA levels are a prominent feature observed in many diseases. However, these changes in RNA biology per se do not cause the disease. I discuss disease-causing mechanisms in the second part of this review. Finally, I briefly summarize possible treatment avenues to counter RNA-based disease mechanism.

Section snippets

RNA in Disease

Classically, neurodegeneration has been tightly linked to protein aggregation. In most neurodegenerative diseases, certain types of aggregates or inclusions are visible under the microscope [3]. Interestingly, mutations in proteins like tau [microtubule-associated protein tau (MAPT)] are found in several of these diseases and most probably change the spectrum of clinical representation [4].

Another hallmark feature is transcriptional dysregulation, which leads to changes in the expression levels

Altered protein homeostasis

The most straightforward mechanism of RNA-based pathology is loss of function. Here, mutations in the DNA (point mutations or insertions/deletions) lead either to degradation of the RNA or expression of different protein isoforms. While this results in the same RNA loss-of-function phenotypes as caused by stochastic transcription errors introduced by RNA polymerases (see above), DNA mutations lead to 100% penetrance. This means that every single RNA molecule exhibits the mutation and thus the

Therapies Targeting RNA-based Disease Mechanisms

Each newly identified mechanism of RNA-based toxicity potentially opens up a new therapeutic point of application. For example, if one could interfere with the just described mechanism of increased translation of CAG containing RNAs, one might alleviate the disease burden by reducing the disease-causing protein. So far, only in silico and first cell culture experiments have been published using an inhibitor of the MID1/CAG RNA complex [111]. Nonetheless, this shows the feasibility of such an

Conclusion

Since the discovery of differences between “animal” and “plant” nucleic acids and the coining of the terms DNA and RNA over 70 years ago [117], a wealth of new functions of RNA in cellular homeostasis has emerged. Despite decades of research, there are still novel roles of RNA to uncover. As an example, most recently, the analysis of the biophysical properties of RNA assemblies has shed new light onto possible ways in which RNA could lead to the formation of subcellular structures.

This review

Acknowledgments

The author appreciates and apologizes that many important studies, which have contributed or led up to knowledge described here, have not been cited. This work was funded by an EHDN seed fund (project 871) to A. Neueder.

Declarations of Interest: None.

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