BioProject

Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. More...

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. Overall design: 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. Less...