ReviewAberrant RNA processing events in neurological disorders
Introduction
The vast majority of neurological diseases are characterised by the presence of abnormal protein aggregates. These lesions can be in the form of extracellular protein deposits that develop as senile plaques or as intracellular inclusions within the cell bodies, nuclei and processes of neurones. As a result of these defining pathological features, neurological diseases are often thought of as diseases of protein metabolism. However, increasing evidence highlights the importance of defective RNA processing in disorders of the nervous system. For example, the RNA-binding protein TDP-43 is a major component of inclusions characteristic of a number of neurodegenerative conditions including ALS (Arai et al., 2006, Kwong et al., 2008, Neumann et al., 2006). Furthermore, mutations in the TDP-43 gene, as well as in the FUS gene, also encoding an RNA-binding protein, have been identified thus confirming their pathological importance (Kwiatkowski et al., 2009, Lagier-Tourenne & Cleveland, 2009, Sreedharan et al., 2008, Vance et al., 2009).
Eukaryotic pre-messenger (m)RNA undergoes extensive post-transcriptional processing through a series of tightly coupled events such as capping, splicing and polyadenylation which protect the transcript on its journey to the cytoplasm and enhance the initiation of translation. In addition, it is thought that the complexity of the human proteome is brought about through processes such as alternative splicing and RNA editing which alter the coding capacity of a transcript. Whilst aberrant alternative splicing has been well documented in neurological disease (Gallo et al., 2005, Licatalosi & Darnell, 2006), it is evident that other RNA processing events such as RNA editing and polyadenylation are also disrupted in some disorders (Abu-Baker & Rouleau, 2007, Kawahara et al., 2004). The purpose of this review is to briefly review RNA processing and detail aberrations in a variety of these intricately coupled events that are involved in neurological disease.
Section snippets
Post-transcriptional mRNA processing
From its transcription in the nucleus to its eventual translation in the cytoplasm, RNA is accompanied by a myriad of proteins that control and regulate its fate. Eukaryotic pre-mRNA must undergo multiple post-transcriptional processing events such as capping, splicing and polyadenylation, and although these classical steps are described sequentially, they occur co-transcriptionally in the nucleus whereby multiple mRNA processing factors are recruited to the C-terminal domain (CTD) of RNA
RNA editing
One hypothesis for the selective degeneration and death of motor neurones in sporadic ALS is a vulnerability of motor neurones to AMPA receptor-mediated excitotoxicity (Van Den Bosch et al., 2006). The calcium permeability of the GluR2 receptor subunit is regulated by a virtually 100% efficient A-to-I RNA editing event which converts a glutamine to an arginine (the Q/R site) in a transmembrane domain of the protein (Sommer et al., 1991). Defective RNA editing at the Q/R site results in neuronal
Concluding remarks
It has become increasingly apparent that aberrant RNA processing plays a role in a wide spectrum of neurological diseases. Whilst disorders such as SMA and DM have long been established as diseases of RNA metabolism, a definite role for aberrant RNA processing in the pathogenesis of other diseases is emerging. In the case of ALS, aberrations in several RNA processing events could account for both familial and sporadic forms of the disease firmly establishing ALS as a disease of RNA processing.
References (121)
- et al.
Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies
Biochim. Biophys. Acta
(2007) - et al.
Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia
Brain Res.
(1995) - et al.
Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons
Cell
(2008) - et al.
TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Biochem. Biophys. Res. Commun.
(2006) - et al.
Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions
Biochimie
(2006) - et al.
TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing
J. Biol. Chem.
(2008) - et al.
Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system
Neuron
(1993) - et al.
TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing
J. Biol. Chem.
(2005) Elongation factor 1 alpha, translation and the cytoskeleton
Trends Biochem. Sci.
(1995)- et al.
Oculopharyngeal muscular dystrophy: potential therapies for an aggregate-associated disorder
Int. J. Biochem. Cell Biol.
(2006)
The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases
Neurosci. Res.
The ribonucleic acid of axons and myelin sheaths from Mauthner neurons
Biochim. Biophys. Acta
Characterization of an RNA granule from developing brain
Mol. Cell. Proteomics
Decreased levels of myotonic dystrophy protein kinase (DMPK) and delayed differentiation in human myotonic dystrophy myoblasts
Neuromuscul. Disord.
Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims
Neuron
The fragile-X premutation: a maturing perspective
Am. J. Hum. Genet.
New insights into fragile X syndrome: from molecules to neurobehaviors
Trends Biochem. Sci.
Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome
Neuron
NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation
Curr. Biol.
Kinesin transports RNA: isolation and characterization of an RNA-transporting granule
Neuron
hnRNP complexes: composition, structure, and function
Curr. Opin. Cell Biol.
Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation
Mol. Cell
Rethinking ALS: the FUS about TDP-43
Cell
Alternative splicing in the nervous system: an emerging source of diversity and regulation
Biol. Psychiatry
Splicing regulation in neurologic disease
Neuron
Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis
Neuron
pH, EF-1alpha and the cytoskeleton
Trends Cell Biol.
RNA editing, DNA recoding and the evolution of human cognition
Trends Neurosci.
The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts
Neurobiol. Dis.
Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway
Am. J. Hum. Genet.
Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway
Am. J. Hum. Genet.
RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy
Neuropsychopharmacology
Immuno-characterization of the switch of peptide elongation factors eEF1A-1/EF-1alpha and eEF1A-2/S1 in the central nervous system during mouse development
Brain Res. Dev. Brain Res.
Capping of eucaryotic mRNAs
Cell
RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS
Neuron
RNA editing in brain controls a determinant of ion flow in glutamate-gated channels
Cell
TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein
Mol. Cell. Neurosci.
eEF1A2 and neuronal degeneration
Biochem. Soc. Trans.
RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1
Nat. Cell Biol.
The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus
Proc. Natl. Acad. Sci. U. S. A.
The central MHC gene, BAT1, may encode a protein that down-regulates cytokine production
Genes Cells
Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis
Hum. Mol. Genet.
Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes
Neurology
Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease
Front. Biosci.
Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA
Hum. Mol. Genet.
Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1
Nat. Genet.
Listening to silence and understanding nonsense: exonic mutations that affect splicing
Nat. Rev. Genet.
Zipcodes and postage stamps: mRNA localisation signals and their trans-acting binding proteins
Brief Funct. Genomic Proteomic
XLMR genes: update 2007
Eur. J. Hum. Genet.
Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo
Nucleic Acids Res.
Cited by (68)
The conserved alternative splicing factor caper regulates neuromuscular phenotypes during development and aging
2021, Developmental BiologyCitation Excerpt :Indeed, transcriptomic analyses have revealed that changes in RNA splicing and RNA processing are strongly correlated with aging (DeschĆŖnes and Chabot, 2017; Wang et al., 2018). Defects in alternative splicing have also emerged as a common theme in aging-related diseases including vascular aging, accelerated aging (progeria), Alzheimerās disease, amyotrophic lateral sclerosis, frontotemporal lobar dementia, and myotonic dystrophy (Anthony and Gallo, 2010; DeschĆŖnes and Chabot, 2017; Doxakis, 2014; Lemmens et al., 2010; Licatalosi and Darnell, 2006; Mills and Janitz, 2012; Strong, 2010; Tazi et al., 2009). There is a well-established link between aging and a gradual decline in locomotor activity across metazoa.
Pre-mRNA splicing defects and RNA binding protein involvement in Niemann Pick type C disease
2020, Journal of BiotechnologyHepatitis, testicular degeneration, and ataxia in DIDO3-deficient mice with altered mRNA processing
2022, Cell and BioscienceCould Amyloid-Ī² 1-42 or Ī±-Synuclein Interact Directly with Mitochondrial DNA? A Hypothesis
2022, ACS Chemical Neuroscience