TDP‐43 promotes pathological tau phosphorylation and selective neurotoxicity in C. elegans

TDP-43-positive inclusions are present in disease-affected neurons in over half of patients with Alzheimer's disease (AD). AD patients with TDP-43 pathology have worsened clinical outcomes and increased neurodegeneration, but the molecular mechanisms underlying this are unknown.We have developed new models of multi-pathology AD by combining tau and TDP-43 or tau and Aβ in C. elegans neurons. To characterize these transgenic animals, we measured changes in behavioral outcomes, pathological protein accumulation, and neuron loss. We further tested whether the potent tau modifier sut-2 influences synergistic neurotoxicity exhibited by tau and TDP-43 co-expression.TDP-43 promotes tau but not Aβ neurotoxicity, resulting in enhanced uncoordinated locomotion, neuronal dysfunction, pathological protein accumulation, and selective neurodegeneration through aging. Synergism between tau and TDP-43 is rescued by sut-2 loss-of-function.Characterizing the relationship between TDP-43 and tau in vivo is critical to understand and ultimately treat mixed pathology AD. Studies of this novel model of tau and TDP-43 combined proteotoxicity provide insights into mechanisms underlying tau and TDP-43 synergistic neurotoxicity. The identification of sut-2 as a robust modifier of co-expressed tau and TDP-43 implicates TDP-43 as an enhancer of tau toxicity.