Respiration enhances TDP-43 toxicity, but TDP-43 retains some toxicity in the absence of respiration

The trans-activating response DNA-binding protein 43 (TDP-43) is a transcriptional repressor and splicing factor. TDP-43 is normally mostly in the nucleus, although it shuttles to the cytoplasm. Mutations in TDP-43 are one cause of familial amyotrophic lateral sclerosis (ALS). In neurons of these patients, TDP-43 forms cytoplasmic aggregates. In addition, wild-type TDP-43 is also frequently found in neuronal cytoplasmic aggregates in patients with neurodegenerative diseases not caused by TDP-43 mutations. TDP-43 expressed in yeast causes toxicity and forms cytoplasmic aggregates. This disease model has been validated because genetic modifiers of TDP-43 toxicity in yeast have led to the discovery that conserved genes in humans are ALS genetic risk factors. While it is still unknown how TDP-43 is associated with toxicity, several studies find that TDP-43 alters mitochondrial function. We now report that TDP-43 is much more toxic when yeast is grown in non-fermentable media requiring respiration than when grown on fermentable carbon sources. However, we also establish that TDP-43 remains toxic in the absence of respiration. Thus, there is a TDP-43 toxicity target in yeast distinct from respiration and respiration is not required for this toxicity. Since we find that H2O2 increases the toxicity of TDP-43, the free oxygen radicals associated with respiration could likewise enhance the toxicity of TDP-43. In this case, the TDP-43 toxicity targets in the presence or absence of respiration could be identical, with the free radical oxygen species produced by respiration activating TDP-43 to become more toxic or making TDP-43 targets more vulnerable.\n\nHighlightsO_LITDP-43 toxicity and aggregation is enhanced when yeast are grown in media that requires respiration.\nC_LIO_LIRespiration is not the sole target of TDP-43 toxicity because TDP-43 still aggregates and is toxic in cells that are not respiring.\nC_LIO_LIHydrogen peroxide enhances TDP-43 toxicity in the absence of respiration suggesting that reactive oxygen species (ROS) produced by respiration may likewise enhance TDP-43 toxicity.\nC_LIO_LIROS could activate TDP-43 to become more toxic or make TDP-43 targets more vulnerable.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/415893_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@85d24aorg.highwire.dtl.DTLVardef@1b103d3org.highwire.dtl.DTLVardef@72280dorg.highwire.dtl.DTLVardef@a3a82e_HPS_FORMAT_FIGEXP M_FIG C_FIG