| First Author | Swarup V | Year | 2011 |
| Journal | J Exp Med | Volume | 208 |
| Issue | 12 | Pages | 2429-47 |
| PubMed ID | 22084410 | Mgi Jnum | J:178611 |
| Mgi Id | MGI:5299364 | Doi | 10.1084/jem.20111313 |
| Citation | Swarup V, et al. (2011) Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways. J Exp Med 208(12):2429-47 |
| abstractText | 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 kappaB (NF-kappaB) 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-kappaB 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-kappaB activation and that NF-kappaB may constitute a therapeutic target for the disease. |
