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.
    The Italian Journal of Neurological Sciences 08/2015; DOI:10.1016/j.jns.2015.07.036
    • "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.
    Cell Reports 07/2015; 126(2). DOI:10.1016/j.celrep.2015.06.019 · 8.36 Impact Factor
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    • "By contrast, BBG fails to affect the astrocytic, GFAP-positive, counterpart of neuroinflammation. The P2X7-microglia correlation is strengthened further by the significant downregulation of NF-κB by the BBG100 protocol, consistent with the notion that NF-κB is upregulated particularly in SOD1-G93A spinal cord microglia (Butovsky et al., 2012; Swarup et al., 2011). Activation of the NF-κB system is also known to trigger, predominantly in microglia, the expression of proinflammatory factors, such as NOX2, IL-1β and TNF-α (Pugazhenthi et al., 2013), and to regulate genes associated with the M2 phenotype, such as BDNF (Kairisalo et al., 2009) and IL-10 (Kobayashi et al., 2013). "
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