a conserved cytoskeletal signaling cascade mediates neurotoxicity of ftdp-17 tau mutations in vivo

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (ftdp-17), which is caused by mutations in tau. in vitro, ftdp-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo. we express wild-type human tau and five ftdp-17 mutant forms of tau in drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. we then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. we find that ftdp-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the ftdp-17 mutants tested. finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various ftdp-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and ftdp-17 mutant tau in disease pathogenesis.