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Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo
Open accessAbstract
Tau is a microtubule binding protein implicated in a number of human neurodegenerative disorders, including Alzheimer's disease. Phosphorylation of serine-proline/threonine-proline sites, targeted by proline-directed kinases, coincides temporally with neurodegeneration in the human diseases. Recently, we demonstrated that this unique group of serines and threonines has a critical role in controlling tau toxicity in a Drosophila model of tauopathy. Here, we use a combination of genetic and biochemical approaches to examine these sites individually and to determine which of them is primarily responsible for controlling tau neurotoxicity. Despite the importance placed on individual phosphoepitopes and their contributions to disease pathogenesis, our results indicate that no single phosphorylation residue plays a dominant role in controlling tau toxicity. These findings suggest that serine-proline/threonine-proline sites cooperate to mediate neurodegeneration in vivo.
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“in vivo fly models of tau toxicity using phosphorylation-resistant tau constructs show equivalent or even increased toxicity when compared with wild-type tau (41,42).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [41]
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“when either 5 (41) or 11 (42) putative GSK-3β phosphorylation sites were mutated to alanine, tau toxicity either comparable to or more robust than the toxicity induced by wild-type tau was still observed.”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [41]
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“In addition, neuronal phenotypes of tau transgenic Drosophila mimic features of human Alzheimer’s disease and associated tauopathies, including but not limited to aberrant tau phosphorylation13, oxidative stress14, DNA damage15,16, decondensation of constitutive heterochromatin10, synaptic dysfunction17 and activation of the cell cycle in post-mitotic neurons18.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [13]
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Metadata
- Authors
- Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L., & Feany, M. B.
- Affiliations
- Central Michigan University (US)
- Brigham and Women's Hospital (US)
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and
- Venue
- Molecular Biology of the Cell
- Published
- 2007-12
- Volume
- 18
- Issue
- 12
- Pages
- 5060-5068
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2096612
- OpenAlex
- W2165049228
- Cited by
- 187
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 16 · 2020: 5 · 2019: 13 · 2018: 4 · 2017: 11 · 2016: 7 · 2015: 14 · 2014: 15 · 2013: 14 · 2012: 9
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG-19790, P50AG005134, AG 05134, R01AG019790)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau phosphorylation, proline-directed kinases, tauopathy, Alzheimer's disease, Drosophila model, neurodegeneration, microtubule-binding protein
- MeSH terms
- Amino Acids, Animals, Cell Cycle, Drosophila melanogaster, Electrophoresis, Polyacrylamide Gel, Mutation, Neurons, Phosphorylation, Protein Kinases, Signal Transduction, tau Proteins, Phosphatidylinositol 3-Kinases, Drosophila Proteins, Animals, Genetically Modified, TOR Serine-Threonine Kinases
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