Erratum published on 12 August 2016,
see
Biomolecules 2016, 6(3), 35.
Biomolecules 2016, 6(2), 19; doi:10.3390/biom6020019
Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease
1
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
2
Medical Research Council Cambridge Brain Bank Laboratory, Department of Psychiatry, University of Cambridge, Cambridge CB2 2QH, UK
3
TauRx Therapeutics Ltd. and School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Scotland AB25 2ZP, UK
†
Current address: Queen Elizabeth II Hospital, Howlands, Welwyn Garden City, Herts AL7 4HQ, UK.
*
Author to whom correspondence should be addressed.
Academic Editor: Jürg Bähler
Received: 13 December 2015 / Revised: 20 March 2016 / Accepted: 31 March 2016 / Published: 8 April 2016
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Abstract
Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. View Full-TextKeywords:
Alzheimer’s disease; tau protein; phosphorylation; protein aggregation
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Lai, R.Y.K.; Harrington, C.R.; Wischik, C.M. Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease. Biomolecules 2016, 6, 19.
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