Swarup V, Phaneuf D, Dupré N, Petri S, Strong M, Kriz J, Julien JP.
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.
J Exp Med. 2011 Nov 21;208(12):2429-47.
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Mutations in TDP-43, a DNA/RNA-binding protein, cause an inherited form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The work by J.P. Julien and colleagues very elegantly shows a linkage between the abnormal regulation of TDP-43 and the pathogenic pathways in ALS, and the researchers attributed it to the activation of p65 NF-κB. The linkage between microglial enhanced toxicity and overexpression of TDP-43 was demonstrated in vitro. Interestingly, overexpression of TDP-43 in neurons caused increased vulnerability to toxicity. The therapeutic potential was demonstrated by in-vivo treatment of TDP-43 transgenic mice with an inhibitor of NF-κB that reduced inflammation and ameliorated motor deficits. This study thus opens up a new potential target for therapeutic intervention in ALS.
Importantly, this is the first report demonstrating an upregulation of mRNAs encoding TDP-43 in postmortem frozen spinal cords of sporadic ALS patients.