Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominates.

Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression. We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that tau related changes largely resemble tau/TDP-43 changes. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD. C.elegans animals expressing pan-neuronal human wild-type tau, human wild-type TDP-43 and aniamls expressing both wild-type human tau and TDP-43 were used in this study. N2 were the controls. To examine transcriptomic changes occuring prior and after the neurodegeneration, RNA was collected from all genotypes at L2 and L4 stage.