Pseudohyperphosphorylation Has Differential Effects on Polymerization and Function of Tau Isoforms
- 26 September 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 50 (44), 9446-9456
- https://doi.org/10.1021/bi2010569
Abstract
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.Keywords
This publication has 59 references indexed in Scilit:
- The frontotemporal dementia mutation R406W blocks tau’s interaction with the membrane in an annexin A2–dependent mannerThe Journal of cell biology, 2011
- Pseudohyperphosphorylation Causing AD-like Changes in Tau Has Significant Effects on Its PolymerizationBiochemistry, 2009
- GSK-3β phosphorylation of functionally distinct tau isoforms has differential, but mild effectsMolecular Neurodegeneration, 2009
- Pre-assembled tau filaments phosphorylated by GSK-3b form large tangle-like structuresNeurobiology of Disease, 2008
- Site-specific Phosphorylation and Caspase Cleavage Differentially Impact Tau-Microtubule Interactions and Tau AggregationJournal of Biological Chemistry, 2006
- Site‐specific pseudophosphorylation modulates the rate of tau filament dissociationFEBS Letters, 2005
- Tau Polymerization: Role of the Amino TerminusBiochemistry, 2003
- Structural and Functional Differences between 3-Repeat and 4-Repeat Tau IsoformsJournal of Biological Chemistry, 2000
- Tau protein kinase I/GSK-3Β/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brainProtein Journal, 1995
- Interpretation of the light scattering from long rodsJournal of Molecular Biology, 1974