TDP-43 Drives Nuclear Factor- B Activation in ALS (P03.179)

Objective: Our objective was to search for proteins which might interact with TDP-43 and to investigate the physiological significance of such interaction. Background TDP-43 inclusions are a hallmark of amyotrophic lateral sclerosis (ALS) and dominant mutations in TARDBP, which codes for TDP-43, were reported by several groups as a primary cause of ALS. However, the physiological role of TDP-43 and the pathogenic pathways of TDP-43 abnormalities are not well understood. Design/Methods: Real-time RT-PCR and ELISA revealed that the levels of mRNA and protein for TDP-43 was elevated in the spinal cord of sporadic ALS cases. Mass spectrometry and co-immunoprecipitation assays were carried out to identify proteins which interact with TDP-43. Transgenic mice overexpressing human TDP-43 by 3 folds and control littermates were used as a source of primary cells and for therapeutic testing of withaferin A. Results: We have found that TDP-43 and NF-κB p65 mRNA and protein expression is higher in spinal cords if 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. Conclusions: We conclude 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. Supported by: The Canadian Institutes of Health Research (CIHR) and Neuromuscular Research Partnership, the Robert Packard Center for ALS Research at Johns Hopkins and the Fondation Andre-Delambre. Disclosure: Dr. Julien has received personal compensation for activities with Biogen Idec as a consultant. Dr. Swarup has nothing to disclose. Dr. Dupre has nothing to disclose. Dr. Kriz has nothing to disclose.

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