A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo
dc.contributor.author | Bardai, Farah H. | |
dc.contributor.author | Wang, Liqun | |
dc.contributor.author | Mutreja, Yamini | |
dc.contributor.author | Yenjerla, Mythili | |
dc.contributor.author | Gamblin, Truman Christopher | |
dc.contributor.author | Feany, Mel B. | |
dc.date.accessioned | 2019-11-15T15:05:29Z | |
dc.date.available | 2019-11-15T15:05:29Z | |
dc.date.issued | 2018-01-03 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/29763 | |
dc.description.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. | en_US |
dc.description.sponsorship | This work wassupported by National Institutes of Health-National Institute of Neurological Disorders and Stroke Grant R01-NS-083391 | en_US |
dc.publisher | Society for Neuroscience | en_US |
dc.rights | Copyright © 2018 the authors Authors grant JNeurosci a license to publish their work and copyright remains with the author. For articles published after 2014, the Society for Neuroscience (SfN) retains an exclusive license to publish the article for 6 months; after 6 months, the work becomes available to the public to copy, distribute, or display under the terms of the Creative Commons Attribution 4.0 International License (CC-BY). This license allows data and text mining, use of figures in presentations, and posting the article online, provided that the original article is credited. | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Alzheimer's | en_US |
dc.subject | Dropsophila | en_US |
dc.subject | tau | en_US |
dc.title | A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Gamblin, Truman Christopher | |
kusw.kuauthor | Mutreja, Yamini | |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.1523/JNEUROSCI.1550-17.2017 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-1998-2572 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | OpenAccess | en_US |
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Authors grant JNeurosci a license to publish their work and copyright remains with the author. For articles published after 2014, the Society for Neuroscience (SfN) retains an exclusive license to publish the article for 6 months; after 6 months, the work becomes available to the public to copy, distribute, or display under the terms of the Creative Commons Attribution 4.0 International License (CC-BY). This license allows data and text mining, use of figures in presentations, and posting the article online, provided that the original article is credited.