Elsevier

Brain Research

Volume 1462, 26 June 2012, Pages 3-15
Brain Research

Review
Misregulated RNA processing in amyotrophic lateral sclerosis

https://doi.org/10.1016/j.brainres.2012.02.059Get rights and content

Abstract

Amyotrophic lateral sclerosis (ALS) research is undergoing an era of unprecedented discoveries with the identification of new genes as major genetic causes of this disease. These discoveries reinforce the genetic, clinical and pathological overlap between ALS and frontotemporal lobar degeneration (FTLD). Common causes of these diseases include mutations in the RNA/DNA-binding proteins, TDP-43 and FUS/TLS and most recently, hexanucleotide expansions in the C9orf72 gene, discoveries that highlight the overlapping pathogenic mechanisms that trigger ALS and FTLD. TDP-43 and FUS/TLS, both of which participate in several steps of RNA processing, are abnormally aggregated and mislocalized in ALS and FTLD, while the expansion in the C9orf72 pre-mRNA strongly suggests sequestration of one or more RNA binding proteins in pathologic RNA foci. Hence, ALS and FTLD converge in pathogenic pathways disrupting the regulation of RNA processing.

This article is part of a Special Issue entitled RNA-Binding Proteins.

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

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