Dynamic association of tau with neuronal membranes is regulated by phosphorylation
Abstract
Tau is an abundant cytosolic protein which regulates cytoskeletal stability by associating with microtubules in a phosphorylation-dependent manner. We have found a significant proportion of tau is located in the membrane fraction of rat cortical neurons and is dephosphorylated, at least at Tau-1 (Ser199/Ser202), AT8 (Ser199/Ser202/Thr205) and PHF-1 (Ser396/Ser404) epitopes. Inhibition of tau kinases casein kinase 1 (CK1) or glycogen synthase kinase-3 decreased tau phosphorylation and significantly increased amounts of tau in the membrane fraction. Mutation of serine/threonine residues to glutamate to mimic phosphorylation in the N-terminal, but not C-terminal, region of tau prevented its membrane localization in transfected cells, demonstrating that the phosphorylation state of tau directly impacts its localization. Inhibiting CK1 in neurons lacking the tyrosine kinase fyn also induced tau dephosphorylation but did not affect its membrane association. Furthermore, inhibition of CK1 increased binding of neuronal tau to the fyn-SH3 domain. We conclude that trafficking of tau between the cytosol and the neuronal membrane is dynamically regulated by tau phosphorylation through a mechanism dependent on fyn expression.
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Phosphorylation can alter tau subcellular localization to dendritic spines or alter its affinity for the plasma membrane, thereby causing alterations in synaptic function.
“Apart from its effects on microtubule binding, phosphorylation can alter tau subcellular localization to dendritic spines (127) or can alter its affinity for the plasma membrane (128), thereby causing alterations in synaptic function (127,129).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [128]
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- Authors
- Pooler, A. M., Usardi, A., Evans, C. J., Philpott, K. L., Noble, W., & Hanger, D. P.
- Affiliations
- King's College London (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Pooler, Amy M.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 33
- Issue
- 2
- Pages
- 431.e27-431.e38
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2011813094
- Cited by
- 148
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 15 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 16 · 2016: 10 · 2015: 15 · 2014: 12 · 2013: 16 · 2012: 5
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- tau protein, tau phosphorylation, tau dephosphorylation, casein kinase 1, glycogen synthase kinase-3, Fyn tyrosine kinase, Fyn SH3 domain, cortical neurons, microtubule stabilization
- MeSH terms
- Animals, Animals, Newborn, Cell Membrane, Cells, Cultured, Neurons, tau Proteins, Rats, Sprague-Dawley, Glycogen Synthase Kinase 3, Casein Kinase I, Rats
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