RNA-mediated toxicity in neurodegenerative disease☆
Introduction
Neurodegenerative diseases represent a large and heterogeneous spectrum of illnesses caused by the progressive loss of neurons in the central or peripheral nervous system. They can largely be classified into two clinical groups: motor/movement disorders and dementia/cognitive impairments. The motor/movement group can be further classified into clinical subgroups, which include motor neuron diseases, Parkinsonism, ataxia and hyperkinesia. The dementia/cognitive impairments group can be divided into two categories, with cognition/memory deficits characterizing one category and personality, behavioral and language impairments characterizing the other.
While distinct mechanisms contribute to each disorder, it is becoming increasingly apparent that abnormalities in RNA processing represent a common feature among many neurodegenerative diseases. Normal cellular function depends on numerous protein-coding and non-coding RNAs, as well as RNA-binding proteins that associate with RNAs to form ribonucleoprotein (RNP) complexes. Mutations or abnormalities that disrupt RNA or protein components of RNP complexes can be deleterious to cells and cause disease. For instance, some neurodegenerative diseases result from mutated coding and non-coding RNAs, and misregulation of long non-coding RNA transcription. Multiple mechanisms are now recognized as driving pathogenesis in these “RNAopathies”, including a toxic gain of function caused by RNAs with nucleotide repeat expansions and the formation of nuclear RNA foci, as well as loss of function caused by gene silencing and haploinsufficiency. However, much less is known regarding the mechanisms underlying “RNA-binding proteinopathies”, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which RNA-binding proteins play a prominent role. Such proteins include transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), which form cytoplasmic and nuclear inclusions in disease. It is believed that the abnormal aggregation of TDP-43 and FUS results in a toxic gain of function conferred by the inclusions themselves, as well as a loss of function caused by the sequestration of these RNA-binding proteins. An extensive list of diseases caused by pathological RNA processes is provided in Table 1.
This review, while not intended to provide an exhaustive characterization of all RNAopathies and RNA-binding proteinopathies, aims to highlight the diverse RNA-related mechanisms contributing to disease pathogenesis, with a special emphasis on findings emerging from animal models. Furthermore, we will discuss how our current knowledge of RNAopathies is likely to guide research on C9ORF72-linked ALS and FTD (c9FTD/ALS); this is an area of great interest since the recent discovery that a hexanucleotide repeat expansion in the C9ORF72 gene is the major genetic cause of ALS and FTD (Dejesus-Hernandez et al., 2011, Renton et al., 2011).
Section snippets
Impaired RNA mechanisms in neurodegeneration
Our current understanding of many neurodegenerative diseases has been greatly directed by genetic discoveries. Despite early beliefs that disease-causing mutations are located only in coding regions of genes, it is now well established that mutations in regulatory sequences also influence gene expression and are a significant cause of disease. Indeed, the majority of the transcriptome is composed of noncoding RNAs that participate in numerous physiological activities, such as regulating RNA
RNA-binding proteinopathies
As demonstrated by the above examples, proper RNA processing is required for normal cellular functions, and gene mutations that result in the accumulation of toxic RNA species cause several diseases. In most of the RNAopathies described, a consequence of RNA foci formation is the abnormal sequestration and loss of function of RNA-binding proteins, such as MBLN, emphasizing the involvement of RNA dysregulation in neurodegeneration. Indeed, mutations or abnormalities that directly affect
Concluding remarks
Aberrant functions of RNA and RNA-binding proteins are recurrent themes in neurodegeneration, underscoring the importance of precise RNA metabolism for neuronal survival. Lessons learned from research on each disease have greatly expanded our knowledge for a wide spectrum of neurological disorders. Because of this, it is becoming increasingly apparent that multiple pathogenic mechanisms can act independently or co-exist in neurodegenerative diseases, especially those caused by microsatellite
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The Role of MicroRNAs in Spinocerebellar Ataxia Type 3
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Support: This work was supported by the Mayo Clinic Foundation (LP), National Institutes of Health/National Institute on Aging [R01AG026251 (LP)], National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01 (LP), R01 NS077402 (LP), ES20395-01 (LP), R21 NS074121-01 (TFG)], Amyotrophic Lateral Sclerosis Association (LP), Canadian Institutes of Health Research (VVB), and the Department of Defense [W81XWH-10-1-0512-1 (LP) and W81XWH-09-1-0315AL093108 (LP)].
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These authors contributed equally to this work.