ReviewMisregulated RNA processing in amyotrophic lateral sclerosis
Highlights
► Amyotrophic lateral sclerosis and Frontotemporal lobar degeneration have clinical, genetic and pathological overlap. ► ALS and FTLD converge in pathogenic pathways disrupting the regulation of RNA processing. ► Identification of TDP-43 RNA targets highlights its multifunctional role in RNA processing. ► TDP-43 autoregulation provides a model for a feed-forward mechanism driving disease progression in TDP-43 proteinopathies.
Section snippets
Introduction: ALS and FTLD are linked genetically, clinically and pathologically
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets motor neurons resulting in progressive paralysis and death within a few years from onset. Just like Alzheimer's, Parkinson's and other neurodegenerative diseases, a proportion (~ 10%) of ALS is dominantly inherited, while the remaining 90% (referred to as sporadic) do not have familial history. With the discovery of mutations in the gene encoding superoxide dismutase 1 (SOD1) as causative for 20% of
Misregulated RNA processing is a convergent causative basis for ALS and FTLD
The mechanisms by which TDP-43 and FUS/TLS trigger neurodegeneration are at the earliest stages of investigation and it is at present unresolved as to whether neurodegeneration is due to a loss of function, a gain of toxic property, or a combination of the two arising from their sequestration into nuclear or cytoplasmic aggregates. If we consider the loss of function hypothesis, then the next question is: what are the physiological roles of TDP-43 and FUS/TLS whose interruption occurs in
RNA processing alterations in ALS patients
Early studies have analyzed RNA expression profiles in affected postmortem tissues of sporadic ALS patients. While there is a large variation in the results reported, probably reflecting the heterogeneity in genetic background, disease stage and tissue preservation, neuroinflammatory pathways were uniformly seen activated in patients' spinal cords (Malaspina et al., 2001) and motor cortices (Wang et al., 2006) and cell-death-associated genes are significantly upregulated in isolated motor
Identification of TDP-43 RNA targets highlights its multifunctional role in RNA processing
Recent studies using revolutionary DNA sequencing technologies have provided initial insights on the normal functions of TDP-43 within the central nervous system. Until recently, only candidate approaches could be used to identify the RNA targets for specific RNA-binding proteins or aberrant RNA splice isoforms related to diseases. Advances in DNA sequencing technology have provided powerful tools for exploring gene regulation in remarkable detail. Indeed, using cross-linking,
TDP-43 regulation of its RNA targets converge in long synaptic transcripts and non-coding RNAs
Amidst the plethora of TDP-43 binding sites, it is crucial to determine the functional events that matter the most both physiologically and pathologically. To identify the contribution of TDP-43 in maintaining the levels and splicing patterns of RNAs, antisense oligonucleotide (ASO) silencing was used to deplete TDP-43 within the normal central nervous system of adult mice (Polymenidou et al., 2011). TDP-43 mRNA was degraded via endogenous RNase H digestion, which specifically recognizes
Autoregulatory mechanisms sustain the levels of TDP-43 protein
The multifunctional role and physiological importance of TDP-43 is evidenced by early embryonic lethality in mice with homozygous disruption in the Tardbp gene (Kraemer et al., 2010, Sephton et al., 2010, Wu et al., 2010) and by autoregulatory mechanisms that have evolved to maintain its levels (Ayala et al., 2011, Igaz et al., 2011, Polymenidou et al., 2011, Xu et al., 2010) to avoid toxicity caused by elevated TDP-43 expression (Shan et al., 2010, Tsai et al., 2010, Wils et al., 2010, Xu et
Perspectives and open questions
While we are witnessing a time of remarkable progress in our understanding of the complex roles of TDP-43, FUS/TLS and other RNA binding proteins in the homeostasis and degeneration of the nervous system, there is undeniably a long list of key, outstanding questions that must be addressed in the near future. Included here are what are the FUS/TLS-dependent RNA-processing events and what is the overlap between the TDP-43 and FUS/TLS regulated events? Which, if any, are the RNA binding proteins
Acknowledgments
M.P. was the recipient of a long-term fellowship from the international Human Frontier Science Program Organization. C.L-T. was the recipient of the Milton-Safenowitz post-doctoral fellowship from the Amyotrophic Lateral Sclerosis Association and is supported by a development grant from the Muscular Dystrophy Association. The authors receive support from the National Institute of Neurological Disorders and Stroke, K99NS075216 to M.P. and R37NS27036 to D.W.C, as well as from the National
References (161)
- et al.
A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function
J. Biol. Chem.
(2007) - et al.
cis-requirement for the maintenance of round spermatid-specific transcription
Dev. Biol.
(2006) - 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.
Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads
Neurosci. Lett.
(2005) - et al.
ALS: a disease of motor neurons and their nonneuronal neighbors
Neuron
(2006) - et al.
Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9
J. Biol. Chem.
(2001) - et al.
DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)
Am. J. Hum. Genet.
(2004) - et al.
RNA localisation in the nervous system
Semin. Cell Dev. Biol.
(2007) - et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
Characterization of an RNA granule from developing brain
Mol. Cell Proteomic.
(2006)
Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior
FEBS Lett.
The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology
Curr. Biol.
Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP
Cell
The fragile-X premutation: a maturing perspective
Am. J. Hum. Genet.
Constructing and deconstructing stem cell models of neurological disease
Neuron
Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome
Neuron
TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity
J. Biol. Chem.
Kinesin transports RNA: isolation and characterization of an RNA-transporting granule
Neuron
TDP-43 is a transcriptional repressor: the testis-specific mouse acrv1 gene is a TDP-43 target in vivo
J. Biol. Chem.
Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis
Neuron
TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2
Acta Neuropathol.
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.
Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain
Nat. Struct. Mol. Biol.
The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response
BMC Cell Biol.
TDP-43 regulates its mRNA levels through a negative feedback loop
EMBO J.
TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration
Ann. Neurol.
The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties
Oncogene
FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis
J. Neurol. Neurosurg. Psychiatry
TDP-43 and ubiquitinated cytoplasmic aggregates in sporadic ALS are low frequency and widely distributed in the lower motor neuron columns independent of disease spread
Amyotroph Lateral Scler.
Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease
Hum. Mutat.
Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules
Hum. Mol. Genet.
Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis
Acta Neuropathol.
Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1
Science
Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease
Front. Biosci.
Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping
EMBO J.
Nuclear factor TDP-43 can affect selected microRNA levels
FEBS J.
Rapidly progressive aphasic dementia and motor neuron disease
Ann. Neurol.
Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps
Nature
TDP-43 is recruited to stress granules in conditions of oxidative insult
J. Neurochem.
Feature article: from the cover: a yeast functional screen predicts new candidate ALS disease genes
Proc. Natl. Acad. Sci. U. S. A.
Prion-like disorders: blurring the divide between transmissibility and infectivity
J. Cell Sci.
A role for ubiquilin 2 mutations in neurodegeneration
Nat. Rev. Neurol.
Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis
J. Neurol. Neurosurg. Psychiatry
Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
Nature
TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor
Mol. Cell. Biol.
Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons
Science
ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import
EMBO J.
Nova autoregulation reveals dual functions in neuronal splicing
EMBO J.
Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS
Nature
TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR
Nucleic Acids Res.
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2020, Journal of BiotechnologyCitation Excerpt :Moreover, the presence of mutations in RBPs, can impairs all the pathways already described, spanning from endo-lysosome circuit, autophagy, and neuroinflammation (Hofmann et al., 2019). Different steps of maturation and quality control are involved in the RNA processing events (Lagier-Tourenne et al., 2010; Polymenidou et al., 2012; Anthony and Gallo, 2010), when these go wrong, the consequent aberrant RNA processing can be associated with several neurological diseases (Anthony and Gallo, 2010). Indeed, in neurodegenerative disorders around 50 % of disease-associated mutations can affect pre-mRNA splicing (Fig. 3A) (Anthony and Gallo, 2010).
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These authors contributed equally.