Phosphorylation that Detaches Tau Protein from Microtubules (Ser262, Ser214) Also Protects It against Aggregation into Alzheimer Paired Helical Filaments
Abstract
One of the hallmarks of Alzheimer's disease is the abnormal state of the microtubule-associated protein tau in neurons. It is both highly phosphorylated and aggregated into paired helical filaments, and it is commonly assumed that the hyperphosphorylation of tau causes its detachment from microtubules and promotes its assembly into PHFs. We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. The proline-directed kinases MAPK and GSK3 are known to phosphorylate most Ser-Pro or Thr-Pro motifs in the regions flanking the repeat domain of tau: they induce the reaction with several antibodies diagnostic of Alzheimer PHFs, but this type of phosphorylation has only a weak effect on tau-microtubule interactions and on PHF assembly. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates some sites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. Thus, contrary to expectations, the phosphorylation that detaches tau from microtubules does not prime it for PHF assembly, but rather inhibits it. Likewise, although the phosphorylation sites on Ser-Pro or Thr-Pro motifs are the most prominent ones on Alzheimer PHFs (by antibody labeling), they are only weakly i…
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Phosphorylation of tau on Ser(P)-262 and Ser(P)-356 in adjacent microtubule binding repeats significantly reduces tau affinity for microtubules and renders tau less susceptible to degradation.
“Phosphorylation of tau on Ser(P)-262 and Ser(P)-356 in adjacent microtubule binding repeats significantly reduces the affinity of tau for microtubules and renders tau less susceptible to degradation (11).”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [11]
MARK-2 overexpression in primary neurons reduces tau-induced deficits by alleviating organelle and vesicle transport blockade.
“Furthermore, MARK-2 overexpression in primary neurons reduces tau-induced deficits by alleviating organelle and vesicle transport blockade (40,126).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [126]
In Alzheimer's disease and other tauopathies, tau becomes abnormally hyperphosphorylated, reducing its microtubule affinity and promoting aggregation.
“In Alzheimer’s disease and other tauopathies, tau becomes abnormally hyperphosphorylated, reducing its microtubule affinity and promoting aggregation (Schneider et al., 1999; Cho and Johnson, 2004).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Schneider et al., 1999
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- Authors
- Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Germany
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1999-03-01
- Volume
- 38
- Issue
- 12
- Pages
- 3549-3558
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2136750984
- Cited by
- 564
- References
- 3
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 26 · 2023: 29 · 2022: 16 · 2021: 22 · 2020: 20 · 2019: 28 · 2018: 21 · 2017: 18 · 2016: 14 · 2015: 17 · 2014: 24 · 2013: 22 · 2012: 21
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- 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, phosphorylation, paired helical filaments, Alzheimer's disease, tau aggregation, MARK kinases, protein kinase A, glycogen synthase kinase-3, mitogen-activated protein kinase, proline-directed phosphorylation, hyperphosphorylation
- MeSH terms
- Alzheimer Disease, Humans, Microtubules, Phosphorylation, Repetitive Sequences, Nucleic Acid, Serine, Neurofibrillary Tangles, tau Proteins, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases
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