ReferenceID 3743
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways
J Exp Med
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
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Record Fields
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- Reference Id
- 3743
- Evidence Id
- 20333
- Core Evidence Id
- 20333
- Source Reference Id
- 777
- Herb2 Reference Id
- HBREF001342
- Subject Paper Key
- HBIN048300_22084410
- Pubmed Id
- 22084410
- Doi
- 10.1084/jem.20111313
- Paper Title
- Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways
- Paper Abstract
- 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.
- Journal
- J Exp Med
- Publish Year
- 2011
- Experiment Subject
- tdp-43 mice,glial and neuronal cells from als patients and mice expressing wild-type and mutant tdp-43 transgenes
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways
- Bilingual Status
- semi_complete