Jackson KL, Dayton RD, Orchard EA, Ju S, Ringe D, Petsko GA, Maquat LE, Klein RL. Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis. Gene Ther. 2015 Jan;22(1):20-8. Epub 2014 Nov 6 PubMed.
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Barmada et al. demonstrate that enhancing the non-sense mediated decay pathway rescues toxicity seen by the overexpression of TDP-43 and FUS. This rescue of toxicity is likely through a direct mechanism by which the auto-regulation of TDP-43 and FUS by non-sense mediated decay is enhanced. It would be interesting to know if there are any secondary benefits of UPF1 overexpression by mutating the necessary sequences for autoregulation of either TDP-43 or FUS.
Jackson et al. show that this rescue also occurs in vivo by demonstrating that UPF1 overexpression rescues both viability and phenotypic toxicities seen in a rat model of TDP-43. This suggests that the upregulation of UPF1 or the non-sense mediated decay pathway may be a potential therapeutic strategy in treating ALS patients.View all comments by Brian Freibaum
We believe that UPF1 does, in fact, have beneficial effects on neuronal survival that are independent of TDP43 and/or FUS autoregulation. This is difficult to study by removing the functional autoregulatory sequences from TDP43 or FUS because we would have to alter the endogenous loci in addition to the exogenous cDNA. We are nonetheless attempting to answer this question through global approaches.
We were excited to see the effects of UPF1 in vivo as determined by Jackson et al., and look forward to adapting UPF1 and/or other modifiers of RNA decay into valid therapeutics.View all comments by Sami Barmada
In our paper (Jackson et al., 2015), we measured endogenous levels of TDP-43 mRNA to address auto-regulation. We also carefully studied whether co-expressing two transgenes with AAV resulted in non-specific gene competition. The data in the paper support that neither issue played a role in the beneficial behavioral outcome.
Jackson KL, Dayton RD, Orchard EA, Ju S, Ringe D, Petsko GA, Maquat LE, Klein RL. Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis. Gene Ther. 2015 Jan;22(1):20-8. Epub 2014 Nov 6 PubMed.View all comments by Ronald Klein
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