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A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo
Bardai, Farah H. Wang, Liqun Mutreja, Yamini Yenjerla, Mythili Gamblin, Truman Christopher Feany, Mel B.
Bardai, Farah H.
Wang, Liqun
Mutreja, Yamini
Yenjerla, Mythili
Gamblin, Truman Christopher
Feany, Mel B.
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Abstract
The microtubule binding proteintau is strongly implicated in multiple neurodegenerative disorders, includingfrontotemporal dementia
and parkinsonism linkedto chromosome 17 (FTDP-17), which is caused by mutations intau.In vitro, FTDP-17 mutant versions oftau 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 inDrosophila 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.
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Date
2018-01-03
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Society for Neuroscience
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Keywords
Alzheimer's, Dropsophila, tau
Citation
Farah H. Bardai, Liqun Wang, Yamini Mutreja, Mythili Yenjerla, T. Chris Gamblin, Mel B. Feany
Journal of Neuroscience 3 January 2018, 38 (1) 108-119; DOI: 10.1523/JNEUROSCI.1550-17.2017