While the neuropathology of Alzheimer's disease (AD) is defined by the presence of amyloid beta and tau aggregates, up to 50% of patients also exhibit aggregates of the protein TDP-43. AD patients with TDP-43 pathology have worse cognitive impairment with more rapid decline and some data suggest TDP-43 may synergize with tau pathology. C. elegans has been widely used to study tau and TDP-43 proteotoxicity separately and such efforts have led to the discovery of
sut-2, a gene whose loss-of-function protects against tau neurotoxicity in C. elegans. However, little is known about how tau and TDP-43 interact when co-expressed in the same organism or if there are modifiers that may disrupt that relationship, necessitating models of combined pathology. We have previously shown that co-expression of tau and TDP-43 in the same organism has synergistically deleterious effects. To further explore this relationship we developed a new low-expression C. elegans model of comorbid tau and TDP-43 and found that even at low levels TDP-43 exacerbates tau pathology, resulting in increased pathological protein accumulation as well as enhanced uncoordinated locomotion and progressive neurodegeneration. We highlight the specificity of this synergy by demonstrating that a strain expressing both wild-type human amyloid and TDP-43 is phenotypically no different from strains that express either protein alone. Finally, in order to further probe the mechanisms underlying the synergy between tau and TDP-43 we crossed tau+TDP Tg with a
sut-2 loss-of-function strain, which largely rescued the enhanced phenotype. The ability of this potent modifier of tau to also have an effect on a model of tau and TDP-43 co-expression suggests that it is enhanced tau toxicity, and not TDP-43, that contributes to the synergistic tau+TDP Tg phenotypes. Characterizing the neurotoxic synergies between tau and TDP-43 in vivo will be critical for understanding and treating mixed pathology AD. Employing a novel model of tau and TDP-43 proteotoxicity, these studies provide initial insights into the mechanisms underlying tau and TDP-43 proteotoxic synergy, and establish the utility and tractability of the tau+TDP Tg model for studying comorbid pathology. Ultimately this model will be useful for identifying additional genetic modifiers of mixed tau and TDP-43 neurotoxicity and aid in a deeper dissection of the biology underlying these phenotypes.