Pseudohyperphosphorylation Has Differential Effects on Polymerization and Function of Tau Isoforms
Open accessAbstract
The microtubule-associated protein tau exists as six isoforms created through the splicing of the second, third, and tenth exons. The isoforms are classified by their number of N-terminal exons (0N, 1N, or 2N) and by their number of microtubule-binding repeat regions (3R or 4R). Hyperphosphorylated isoforms accumulate in insoluble aggregates in Alzheimer's disease and other tauopathies. These neurodegenerative diseases can be categorized based on the isoform content of the aggregates they contain. Hyperphosphorylated tau has the general characteristics of an upward electrophoretic shift, decreased microtubule binding, and an association with aggregation. Previously we have shown that a combination of seven pseudophosphorylation mutations at sites phosphorylated by GSK-3β, referred to as 7-Phos, induced several of these characteristics in full-length 2N4R tau and led to the formation of fewer but longer filaments. We sought to determine whether the same phosphorylation pattern could cause differential effects in the other tau isoforms, possibly through varied conformational effects. Using in vitro techniques, we examined the electrophoretic mobility, aggregation properties, and microtubule stabilization of all isoforms and their pseudophosphorylated counterparts. We found that pseudophosphorylation affected each isoform, but in several cases certain isoforms were affected more than others. These results suggest that hyperphosphorylation of tau isoforms could play a major role in determining the isoform composition of tau aggregates in disease.
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4R tau displays a higher propensity for aggregation than 3R tau.
“4R tau does display a higher propensity for aggregation [10] which has led some to postulate that it is more pathogenic [11–13].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [10]
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- Authors
- Combs, B., Voss, K., & Gamblin, T. C.
- Affiliations
- University of Kansas (US)
- Corresponding author
- Gamblin, T. Chris
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-10-17
- Volume
- 50
- Issue
- 44
- Pages
- 9446-9456
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC3224825
- OpenAlex
- W2018116894
- Cited by
- 41
- References
- 60
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2017: 7 · 2016: 3 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 3
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- KU ScholarWorks (University of Kansas) (submittedVersion)
- Funders
- National Institute on Aging (K02AG025898, AG025898, R01AG022428, AG022428)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, tau isoforms, hyperphosphorylation, GSK3β, microtubule stabilization, tau aggregation, Alzheimer's disease, tauopathy, electrophoretic mobility
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Aspartic Acid, Biopolymers, Humans, Phosphorylation, Serine, Threonine, Mutagenesis, Site-Directed, Arachidonic Acid, tau Proteins, Glutamic Acid, Amino Acid Substitution, Protein Isoforms, Tauopathies, Glycogen Synthase Kinase 3
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