Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor B-mediated pathogenic pathways

Department of Psychiatry and Neuroscience, Research Centre of the University Hospital Centre of Quebec, Canada.
Journal of Experimental Medicine (Impact Factor: 12.52). 11/2011; 208(12):2429-47. DOI: 10.1084/jem.20111313
Source: PubMed


TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.

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    • "An increased level of activated NF-κB has been found in the nuclei of oligodendrocytes in active, but not in inactive, MS plaques [33], and equally NF-κB activation has been reported in astrocytes from ALS patients [34]. Moreover, in transgenic mice expressing a mutated form of TDP-43 implicated in ALS, inhibition of NF-κB activity ameliorates clinical symptoms [35]. Therefore, even if the link between NF-kB and the genetic defects analyzed is not well understood, a role of these mutations in its aberrant regulation, as than as in regulation of other genes involved in inflammation, could be supposed. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the χ 2 test with a standard 2 × 2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS.
    No preview · Article · Aug 2015 · The Italian Journal of Neurological Sciences
    • "It will thus be exciting to link the developmental role of these MRs to their function in neurodegeneration. Although, in most instances, NF-kB activation is known for its pro-survival role, several lines of evidence suggest a pathogenic role of this TF in ALS (Akizuki et al., 2013; Jiang et al., 2005; Maruyama et al., 2010; Swarup et al., 2011). Yet, NF-kB inactivation in MNs is not known to abrogate mSOD1 astrocyte-mediated MN death. "
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    ABSTRACT: Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, "interactome"), whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS), characterized by a loss of spinal motor neurons (MNs). Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Cell Reports
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    • "TDP-43 is a 414-amino acid heterogeneous nuclear ribonucleoprotein encoded by the TARDBP gene (Ou et al., 1995), which binds DNA and RNA for multiple functions such as transcriptional repression, pre-messenger RNA splicing, and translational regulation (Buratti and Baralle, 2008; Wang et al., 2008). TDP-43 binds neurofilament light (NF-L) messenger RNA (mRNA) (Strong et al., 2007), stabilizing it and regulating its transcription, and may also have a role in NF-L mRNA metabolism (Swarup et al., 2011) and axonal transport (Alami et al., 2014). "
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    ABSTRACT: The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with aging than the levels of TDP-43 expression. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Oct 2014 · Neurobiology of Aging
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