Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis

Hanger, Diane P.; Byers, Helen L.; Wray, Selina; Leung, Kit-Yi; Saxton, Malcolm J.; Seereeram, Anjan; Reynolds, C. Hugh; Ward, Malcolm A.; Anderton, Brian H.

doi:10.1074/jbc.m703269200

Cited by 455Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Proteomics Techniques and Applications

Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis

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Hanger, Diane P., Byers, Helen L., Wray, Selina, Leung, Kit-Yi, Saxton, Malcolm J., Seereeram, Anjan, Reynolds, C. Hugh, Ward, Malcolm A. +1 more·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m703269200

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Abstract

Tau in Alzheimer disease brain is highly phosphorylated and aggregated into paired helical filaments comprising characteristic neurofibrillary tangles. Here we have analyzed insoluble Tau (PHF-tau) extracted from Alzheimer brain by mass spectrometry and identified 11 novel phosphorylation sites, 10 of which were assigned unambiguously to specific amino acid residues. This brings the number of directly identified sites in PHF-tau to 39, with an additional six sites indicated by reactivity with phosphospecific antibodies to Tau. We also identified five new phosphorylation sites in soluble Tau from control adult human brain, bringing the total number of reported sites to nine. To assess which kinases might be responsible for Tau phosphorylation, we used mass spectrometry to determine which sites were phosphorylated in vitro by several kinases. Casein kinase 1delta and glycogen synthase kinase-3beta were each found to phosphorylate numerous sites, and each kinase phosphorylated at least 15 sites that are also phosphorylated in PHF-tau from Alzheimer brain. A combination of casein kinase 1delta and glycogen synthase kinase-3beta activities could account for over three-quarters of the serine/threonine phosphorylation sites identified in PHF-tau, indicating that casein kinase 1delta may have a role, together with glycogen synthase kinase-3beta, in the pathogenesis of Alzheimer disease.

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More than 45 tau residues were found phosphorylated at higher frequencies in post-mortem brain tissue from Alzheimer's disease patients.
“Of which >45 residues were found to be phosphorylated at higher frequencies in post-mortem brain tissue from Alzheimer’s disease patients (Morishima-Kawashima et al., 1995; Hanger et al., 2007; Hanger et al., 2009; Wesseling et al., 2020).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Hanger et al., 2007
The Results (page not available) report phosphorylated tau sites in post-mortem Alzheimer brain, but count 39 directly identified sites and suggest there may be as many as 45 when antibody evidence is included—not more than 45 residues. The comparison with control brain concerns the number of detectable sites; it does not establish that more than 45 residues were phosphorylated at higher frequencies. (LLM, conf=0.88)
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GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at SP/TP sites.
“GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at serine or threonine followed by proline (i.e., SP/TP sites) [46–49]”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [49]

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Authors: Hanger, D. P., Byers, H. L., Wray, S., Leung, K.-Y., Saxton, M. J., Seereeram, A., Reynolds, C. H., Ward, M. A., & Anderton, B. H.
Affiliations: King's College London (GB)
Corresponding author: Hanger, Diane P.
ORCID: Hanger, Diane P.
Wray, Selina
Leung, Kit-Yi
Ward, Malcolm A.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-08
Volume: 282
Issue: 32
Pages: 23645-23654
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m703269200
OpenAlex: W2018423808
Cited by: 455
References: 4
Citations by year: 2026: 23 · 2025: 20 · 2024: 25 · 2023: 23 · 2022: 23 · 2021: 37 · 2020: 37 · 2019: 18 · 2018: 22 · 2017: 19 · 2016: 18 · 2015: 19 · 2014: 26 · 2013: 26 · 2012: 25
FWCI: 14.15
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4795 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Alzheimer's Society
Medical Research Council
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords: tau protein, phosphorylation sites, Alzheimer's disease, CK1δ, glycogen synthase kinase-3β, paired helical filaments, neurofibrillary tangles, tau aggregation, kinase substrate specificity, human brain
MeSH terms: Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Amino Acid Sequence, Animals, Brain, Humans, Models, Biological, Molecular Sequence Data, Neurons, Protein Binding, Recombinant Proteins, tau Proteins, Protein Isoforms, Glycogen Synthase Kinase 3, Casein Kinase Idelta, Rats

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Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis

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