PMID- 29138281
OWN - NLM
STAT- MEDLINE
DCOM- 20190221
LR  - 20190824
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 38
IP  - 1
DP  - 2018 Jan 3
TI  - A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau 
      Mutations In Vivo.
PG  - 108-119
LID - 10.1523/JNEUROSCI.1550-17.2017 [doi]
AB  - 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.SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and 
      forms insoluble inclusion bodies known as neurofibrillary tangles in the brain 
      tissue of patients with a variety of neurodegenerative disorders, including 
      Alzheimer's disease. The tau protein is thus widely felt to play a key role in 
      promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. 
      Here we capitalize on an "experiment of nature" in which rare missense mutations 
      in tau cause familial neurodegeneration and neurofibrillary tangle formation. By 
      comparing the biochemical activities of different tau mutations with their in 
      vivo toxicity in a well controlled Drosophila model system, we find that all 
      mutations tested increase phosphorylation of tau and trigger a cascade of 
      neurotoxicity critically impinging on the integrity of the actin cytoskeleton.
CI  - Copyright (c) 2018 the authors 0270-6474/18/380108-12$15.00/0.
FAU - Bardai, Farah H
AU  - Bardai FH
AUID- ORCID: 0000-0002-1998-2572
AD  - Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, 
      Boston, Massachusetts 02115, and.
FAU - Wang, Liqun
AU  - Wang L
AD  - Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, 
      Boston, Massachusetts 02115, and.
FAU - Mutreja, Yamini
AU  - Mutreja Y
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045.
FAU - Yenjerla, Mythili
AU  - Yenjerla M
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045.
FAU - Gamblin, T Chris
AU  - Gamblin TC
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045 
      gamblin@ku.edu mel_feany@hms.harvard.edu.
FAU - Feany, Mel B
AU  - Feany MB
AD  - Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, 
      Boston, Massachusetts 02115, and gamblin@ku.edu mel_feany@hms.harvard.edu.
LA  - eng
GR  - R01 NS083391/NS/NINDS NIH HHS/United States
GR  - U54 HD090255/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20171114
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Actins)
RN  - 0 (MAPT protein, human)
RN  - 0 (tau Proteins)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Autophagy
MH  - Conserved Sequence
MH  - *Cytoskeleton
MH  - Drosophila
MH  - Humans
MH  - Mutagenesis, Insertional
MH  - Mutation/*genetics
MH  - Phosphorylation
MH  - Signal Transduction/*genetics
MH  - Tauopathies/*genetics/physiopathology
MH  - Unfolded Protein Response
MH  - tau Proteins/*genetics
PMC - PMC5761430
OTO - NOTNLM
OT  - Alzheimer's
OT  - Drosophila
OT  - tau
EDAT- 2017/11/16 06:00
MHDA- 2019/02/23 06:00
PMCR- 2018/07/03
CRDT- 2017/11/16 06:00
PHST- 2017/06/05 00:00 [received]
PHST- 2017/10/27 00:00 [revised]
PHST- 2017/10/31 00:00 [accepted]
PHST- 2017/11/16 06:00 [pubmed]
PHST- 2019/02/23 06:00 [medline]
PHST- 2017/11/16 06:00 [entrez]
PHST- 2018/07/03 00:00 [pmc-release]
AID - JNEUROSCI.1550-17.2017 [pii]
AID - 1550-17 [pii]
AID - 10.1523/JNEUROSCI.1550-17.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2018 Jan 3;38(1):108-119. doi: 10.1523/JNEUROSCI.1550-17.2017. Epub 
      2017 Nov 14.