Elsevier

Molecular and Cellular Neuroscience

Volume 56, September 2013, Pages 406-419
Molecular and Cellular Neuroscience

RNA-mediated toxicity in neurodegenerative disease

https://doi.org/10.1016/j.mcn.2012.12.006Get rights and content

Abstract

Cellular viability depends upon the well-orchestrated functions carried out by numerous protein-coding and non-coding RNAs, as well as RNA-binding proteins. During the last decade, it has become increasingly evident that abnormalities in RNA processing represent a common feature among many neurodegenerative diseases. In “RNAopathies”, which include diseases caused by non-coding repeat expansions, RNAs exert toxicity via diverse mechanisms: RNA foci formation, bidirectional transcription, and the production of toxic RNAs and proteins by repeat associated non-ATG translation. The mechanisms of toxicity in “RNA-binding proteinopathies”, diseases in which RNA-binding proteins like TDP-43 and FUS play a prominent role, have yet to be fully elucidated. Nonetheless, both loss of function of the RNA binding protein, and a toxic gain of function resulting from its aggregation, are thought to be involved in disease pathogenesis. As part of the special issue on RNA and Splicing Regulation in Neurodegeneration, this review intends to explore the diverse RNA-related mechanisms contributing to neurodegeneration, with a special emphasis on findings emerging from animal models.

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

References (184)

  • H. Doi et al.

    The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases

    Neurosci. Res.

    (2010)
  • G.V. Echeverria et al.

    RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity

    Brain Res.

    (2012)
  • I. Gijselinck et al.

    A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study

    Lancet Neurol.

    (2012)
  • M. Gorospe

    RNA-binding proteins: post-transcriptional control of aging traits: an introduction to a series of review articles

    Ageing Res. Rev.

    (2012)
  • W.K. Hofmann

    Mechanism of action of demethylating and immune modulatory agents–discussion

    Cancer Treat. Rev.

    (2011)
  • R. Janknecht

    EWS-ETS oncoproteins: the linchpins of Ewing tumors

    Gene

    (2005)
  • B.S. Johnson et al.

    TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity

    J. Biol. Chem.

    (2009)
  • R. Koga et al.

    Decreased myotonin-protein kinase in the skeletal and cardiac muscles in myotonic dystrophy

    Biochem. Biophys. Res. Commun.

    (1994)
  • R. Krahe et al.

    Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing

    Genomics

    (1995)
  • N.A. Lanson et al.

    FUS-related proteinopathies: lessons from animal models

    Brain Res.

    (2012)
  • N.D. Merner et al.

    Exome sequencing identifies FUS mutations as a cause of essential tremor

    Am. J. Hum. Genet.

    (2012)
  • K. Moisse et al.

    Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL(-/-)mice: Support for a role for TDP-43 in the physiological response to neuronal injury

    Brain Res.

    (2009)
  • K. Moisse et al.

    Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: Implications for TDP-43 in the physiological response to neuronal injury

    Brain Res.

    (2009)
  • S. Al-Mahdawi et al.

    The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues

    Hum. Mol. Genet.

    (2008)
  • S. Al-Sarraj et al.

    p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS

    Acta Neuropathol.

    (2011)
  • Y.M. Ayala et al.

    Structural determinants of the cellular localization and shuttling of TDP-43

    J. Cell Sci.

    (2008)
  • Y.M. Ayala et al.

    TDP-43 regulates its mRNA levels through a negative feedback loop

    EMBO J.

    (2011)
  • S.J. Barmada et al.

    Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis

    J. Neurosci.

    (2010)
  • A.C. Bell et al.

    Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene

    Nature

    (2000)
  • C.I. Berul et al.

    DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

    J. Clin. Invest.

    (1999)
  • K. Bomsztyk et al.

    hnRNP K: one protein multiple processes

    Bioessays

    (2004)
  • A.L. Boxer et al.

    Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

    J. Neurol. Neurosurg. Psychiatry

    (2011)
  • W.G. Bradley

    Neurology in clinical practice

    (2000)
  • E. Buratti et al.

    Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease

    Front. Biosci.

    (2008)
  • P. Caiafa et al.

    DNA methylation and chromatin structure: the puzzling CpG islands

    J. Cell. Biochem.

    (2005)
  • V. Campuzano et al.

    Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion

    Science

    (1996)
  • A. Cannon et al.

    Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

    Acta Neuropathol.

    (2012)
  • J. Chen et al.

    Over 20% of human transcripts might form sense-antisense pairs

    Nucleic Acids Res.

    (2004)
  • I.C. Chen et al.

    Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci

    BMC Mol. Biol.

    (2009)
  • P.M. Chiang et al.

    Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • C. Colombrita et al.

    TDP-43 is recruited to stress granules in conditions of oxidative insult

    J. Neurochem.

    (2009)
  • J. Cooper-Knock et al.

    Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72

    Brain

    (2012)
  • J.C. Darnell et al.

    FMRP RNA targets: identification and validation

    Genes Brain Behav.

    (2005)
  • R.S. Daughters et al.

    RNA gain-of-function in spinocerebellar ataxia type 8

    PLoS Genet.

    (2009)
  • J.W. Day et al.

    Spinocerebellar ataxia type 8: clinical features in a large family

    Neurology

    (2000)
  • C.M. Dewey et al.

    TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor

    Mol. Cell. Biol.

    (2011)
  • A.C. Elden et al.

    Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

    Nature

    (2010)
  • M. Fardaei et al.

    Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells

    Hum. Mol. Genet.

    (2002)
  • G.N. Filippova et al.

    An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes

    Mol. Cell. Biol.

    (1996)
  • G.N. Filippova et al.

    CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus

    Nat. Genet.

    (2001)
  • Cited by (72)

    • Proteostasis impairment and ALS

      2022, Progress in Biophysics and Molecular Biology
    • RNA toxicity in tandem nucleotide repeats mediated neurodegenerative disorders

      2020, RNA-Based Regulation in Human Health and Disease
    • Assaying RNA solvent accessibility in living cells with LASER

      2020, Methods in Enzymology
      Citation Excerpt :

      Nearly all of the most pressing diseases, such as cancer and neurodegeneration (ALS; FTD; Alzheimer's), can be traced back to RNA dysfunction. For example, long double-stranded repeat RNAs function by sequestering splicing proteins thereby preventing their normal role in alternative splicing (Belzil, Gendron, & Petrucelli, 2013). Faulty RNA structures, due to mutations, can prevent RNA-protein interactions or RNA folding, thereby altering RNA metabolism to result in disease (Zeraati et al., 2017).

    • The Role of MicroRNAs in Spinocerebellar Ataxia Type 3

      2019, Journal of Molecular Biology
      Citation Excerpt :

      Several RNA species play important roles not only in healthy tissue but also in disease development. Thus RNA-mediated toxic mechanisms have been suggested to play a role in pathogenesis [6–10] (Neueder, Tabach, Weydt and Schilling et al. from the upcoming Special Issue). In this review, we will specifically focus on the role of miRNAs in spinocerebellar ataxia type 3 (SCA3).

    • Solving the Puzzle of Neurodegeneration

      2018, The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms
    View all citing articles on Scopus

    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)].

    1

    These authors contributed equally to this work.

    View full text