Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, Shaw C, Chandran S, Finkbeiner S. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014 Aug;10(8):677-85. Epub 2014 Jun 29 PubMed.
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King's College London
This is quite an intricate paper, as is the authors' method for studying TDP-43-mediated toxicity, which speaks to the fact that TDP-43 levels must be regulated carefully (it does of course regulate its own expression). Overall, the study is well done. Perhaps the most significant observation is that inducing autophagy with compounds that could potentially be used in humans seemed to work in human cells in vitro.
In terms of the biology of TDP-43, it is already known that too much of this protein is a bad thing. That the authors quantified this while taking into account cell death and aggregation, which are confounding factors in the study of protein turnover, is an important contribution and may help resolve some previous discrepancies in the literature on mutant TDP-43 half-life. The stability of TDP-43 mutants is still being debated.
For sporadic, or non-familial, ALS (sALS), the paper is highly relevant, as it is based on TDP-43 biology. I don't think it is a coincidence that WT TDP-43 aggregates in sALS, and that TDP-43 gene mutations occur in ALS as well. Whatever results we get with TDP-43 mutations will be highly relevant to sALS, so the implication is that autophagy induction could be of value in sporadic disease. For that reason it is interesting that autophagy induction appeared to reduce levels of non-aggregated TDP-43 as well as aggregated TDP-43. I was not aware that autophagy could have such an effect.
Testing the autophagy effects using in vivo models will be important and should be done in TDP-43 transgenic mice and rats, but negative results from these animal studies should not necessarily stop us from considering FDA approved compounds for use in humans (particularly as rodent models of TDP-43 toxicity are still very much a work in progress).
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