Journal of Molecular Biology
ReviewRNA-Mediated Disease Mechanisms in Neurodegenerative Disorders
Graphical Abstract
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.
References (121)
- et al.
Protein aggregation and neurodegenerative diseases: from theory to therapy
Eur. J. Med. Chem.
(2016) - et al.
Non-coding RNAs—novel targets in neurotoxicity
Neurotoxicology
(2012) - et al.
The mechanism and function of circular RNAs in human diseases
Exp. Cell Res.
(2018) - et al.
A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa
Am. J. Hum. Genet.
(2011) - et al.
A slow RNA polymerase II affects alternative splicing in vivo
Mol. Cell
(2003) - et al.
RNA editing by mammalian ADARs
Adv. Genet.
(2011) - et al.
Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease
Cell
(2013) - et al.
When lamins go bad: nuclear structure and disease
Cell
(2013) - et al.
Accurate translation of the genetic code depends on tRNA modified nucleosides
J. Biol. Chem.
(2002) Repeat expansion diseases
Handb. Clin. Neurol.
(2018)