S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila
Abstract
The microtubule‐associated protein tau is hyperphosphorylated abnormally in AD and related neurodegenerative disorders. Many phospho epitopes created by proline directed kinases (SP/TP sites) show relative specificity for disease states. To test whether phosphorylation at the disease‐associated SP/TP sites affects tau toxicity in vivo, we expressed a form of tau in Drosophila in which all SP/TP sites are mutated to alanine. We find that blocking phosphorylation at SP/TP motifs markedly reduces tau toxicity in vivo. Using phosphorylation‐specific antibodies, we identify a positive correlation between increased phosphorylation at disease‐associated sites and neurotoxicity. We use the phosphorylation‐incompetent version of tau to show that kinase and phosphatase modifiers of tau neurotoxicity, including cdk5/p35, the JNK kinase hemipterous and PP2A act via SP/TP phosphorylation sites. We provide direct evidence in an animal model system to support the role of phosphorylation at SP/TP sites in playing a critical role in tau neurotoxicity. © 2007 Wiley‐Liss, Inc.
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Many disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats.
“Many disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats (Fulga et al., 2007; Steinhilb et al., 2007; Hoover et al., 2010; Wesseling et al., 2020).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Steinhilb et al., 2007
The 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions.
“The 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Steinhilb et al., 2007
Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity.
“Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity [26, 53–56].”
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Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Steinhilb, M. L., Dias‐Santagata, D., Mulkearns, E. E., Shulman, J. M., Biernat, J., Mandelkow, E., & Feany, M. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Max Planck Unit for Structural Molecular Biology (DE)
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2007-03-04
- Volume
- 85
- Issue
- 6
- Pages
- 1271-1278
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2144533748
- Cited by
- 107
- References
- 5
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 8 · 2020: 5 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 5 · 2015: 5 · 2014: 10 · 2013: 6 · 2012: 5
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- McKnight Foundation
- National Institutes of Health
- National Institute on Aging (AG-19790, P50AG005134, AG 05134, R01AG019790)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau hyperphosphorylation, Alzheimer's disease, Drosophila, Cdk5/p35, JNK kinase, protein phosphatase 2A, proline-directed kinases
- MeSH terms
- Alanine, Animals, Disease Models, Animal, Drosophila, Enzyme Activation, Eye, Microscopy, Electron, Scanning, Mutation, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Kinases, tau Proteins, Neurotoxicity Syndromes, Drosophila Proteins, Animals, Genetically Modified, Proline-Directed Protein Kinases
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