PMID- 33965374
OWN - NLM
STAT- MEDLINE
DCOM- 20210831
LR  - 20240216
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 296
DP  - 2021 Jan-Jun
TI  - TBK1 interacts with tau and enhances neurodegeneration in tauopathy.
PG  - 100760
LID - S0021-9258(21)00553-6 [pii]
LID - 10.1016/j.jbc.2021.100760 [doi]
LID - 100760
AB  - One of the defining pathological features of Alzheimer's disease (AD) is the 
      deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau 
      in the brain. Aberrant activation of kinases in AD has been suggested to enhance 
      phosphorylation and toxicity of tau, making the responsible tau kinases 
      attractive therapeutic targets. The full complement of tau-interacting kinases in 
      AD brain and their activity in disease remains incompletely defined. Here, 
      immunoaffinity enrichment coupled with mass spectrometry (MS) identified 
      TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical 
      brain tissues. We validated this interaction in human AD, familial frontotemporal 
      dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations 
      in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain 
      tissues as well as human cell lines. Further, we document increased TBK1 
      activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based 
      on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, 
      activating expression of a conserved TBK1 ortholog triggers tau 
      hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the 
      reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest 
      that increased TBK1 activation may promote tau hyperphosphorylation and neuronal 
      loss in AD and related tauopathies.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Abreha, Measho H
AU  - Abreha MH
AD  - Department of Biochemistry, Emory University School of Medicine, Atlanta, 
      Georgia, USA; Center for Neurodegenerative Diseases, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Ojelade, Shamsideen
AU  - Ojelade S
AD  - Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; Jan and 
      Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 
      Texas, USA.
FAU - Dammer, Eric B
AU  - Dammer EB
AD  - Department of Biochemistry, Emory University School of Medicine, Atlanta, 
      Georgia, USA; Center for Neurodegenerative Diseases, Emory University School of 
      Medicine, Atlanta, Georgia, USA; Department of Pathology and Laboratory Medicine, 
      Emory University School of Medicine, Atlanta, Georgia, USA.
FAU - McEachin, Zachary T
AU  - McEachin ZT
AD  - Center for Neurodegenerative Diseases, Emory University School of Medicine, 
      Atlanta, Georgia, USA; Department of Cell Biology, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Duong, Duc M
AU  - Duong DM
AD  - Department of Biochemistry, Emory University School of Medicine, Atlanta, 
      Georgia, USA; Center for Neurodegenerative Diseases, Emory University School of 
      Medicine, Atlanta, Georgia, USA; Department of Pathology and Laboratory Medicine, 
      Emory University School of Medicine, Atlanta, Georgia, USA.
FAU - Gearing, Marla
AU  - Gearing M
AD  - Center for Neurodegenerative Diseases, Emory University School of Medicine, 
      Atlanta, Georgia, USA; Department of Pathology and Laboratory Medicine, Emory 
      University School of Medicine, Atlanta, Georgia, USA; Department of Neurology, 
      Emory University School of Medicine, Atlanta, Georgia, USA.
FAU - Bassell, Gary J
AU  - Bassell GJ
AD  - Center for Neurodegenerative Diseases, Emory University School of Medicine, 
      Atlanta, Georgia, USA; Department of Cell Biology, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Lah, James J
AU  - Lah JJ
AD  - Center for Neurodegenerative Diseases, Emory University School of Medicine, 
      Atlanta, Georgia, USA; Department of Neurology, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Levey, Allan I
AU  - Levey AI
AD  - Center for Neurodegenerative Diseases, Emory University School of Medicine, 
      Atlanta, Georgia, USA; Department of Neurology, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Shulman, Joshua M
AU  - Shulman JM
AD  - Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; Jan and 
      Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 
      Texas, USA; Department of Molecular and Human Genetics, Baylor College of 
      Medicine, Houston, Texas, USA; Department of Neuroscience, Baylor College of 
      Medicine, Houston, Texas, USA. Electronic address: Joshua.Shulman@bcm.edu.
FAU - Seyfried, Nicholas T
AU  - Seyfried NT
AD  - Department of Biochemistry, Emory University School of Medicine, Atlanta, 
      Georgia, USA; Center for Neurodegenerative Diseases, Emory University School of 
      Medicine, Atlanta, Georgia, USA; Department of Neurology, Emory University School 
      of Medicine, Atlanta, Georgia, USA. Electronic address: nseyfri@emory.edu.
LA  - eng
GR  - P30 AG066511/AG/NIA NIH HHS/United States
GR  - R01 AG050631/AG/NIA NIH HHS/United States
GR  - R01 AG053960/AG/NIA NIH HHS/United States
GR  - U01 AG061357/AG/NIA NIH HHS/United States
GR  - P50 AG025688/AG/NIA NIH HHS/United States
GR  - RF1 AG057470/AG/NIA NIH HHS/United States
GR  - R01 AG057339/AG/NIA NIH HHS/United States
GR  - RF1 AG057471/AG/NIA NIH HHS/United States
GR  - R01 AG061800/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210507
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (MAPT protein, human)
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TBK1 protein, human)
SB  - IM
MH  - Alzheimer Disease/*metabolism/pathology
MH  - Animals
MH  - Drosophila
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - *Protein Interaction Maps
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Tauopathies/*metabolism/pathology
MH  - tau Proteins/*metabolism
PMC - PMC8191334
OTO - NOTNLM
OT  - Alzheimer's disease (AD)
OT  - Drosophila
OT  - IkappaB kinase (IKK)
OT  - TANK-binding kinase 1 (TBK1)
OT  - co-immunoprecipitation (co-IP)
OT  - familial frontotemporal dementia and parkinsonism linked to chromosome 17 
      (FTDP-17)
OT  - mass spectrometry (MS)
OT  - microtubule-associated protein tau (MAPT)
OT  - neurofibrillary tangles (NFTs)
OT  - posttranslational modification (PTM)
COIS- Conflict of interest statement The authors declare that they have no conflicts of 
      interest with the contents of this article.
EDAT- 2021/05/10 06:00
MHDA- 2021/09/01 06:00
PMCR- 2021/05/07
CRDT- 2021/05/09 20:34
PHST- 2020/12/17 00:00 [received]
PHST- 2021/04/29 00:00 [revised]
PHST- 2021/05/05 00:00 [accepted]
PHST- 2021/05/10 06:00 [pubmed]
PHST- 2021/09/01 06:00 [medline]
PHST- 2021/05/09 20:34 [entrez]
PHST- 2021/05/07 00:00 [pmc-release]
AID - S0021-9258(21)00553-6 [pii]
AID - 100760 [pii]
AID - 10.1016/j.jbc.2021.100760 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Jan-Jun;296:100760. doi: 10.1016/j.jbc.2021.100760. Epub 2021 
      May 7.