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Thank you for this well-written article.
I would like to add this recent study, which showed that nucleic acid binding activity is required for TDP-43-mediated toxicity in flies.
C-terminal fragments of TDP-43 lack such activity, but are still capable of forming aggregates. This supports the hypothesis that the aggregates themselves are not toxic, and that instead, the toxicity is related to a modulation of the endogenous function of this nucleic acid binding protein.
Therefore, studies addressing its DNA and RNA targets may be very important in understanding TDP-43-mediated neurodegeneration.
Voigt A, Herholz D, Fiesel FC, Kaur K, Müller D, Karsten P, Weber SS, Kahle PJ, Marquardt T, Schulz JB.
TDP-43-mediated neuron loss in vivo requires RNA-binding activity.
PLoS One. 2010;5(8):e12247.