Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer's Disease

Robert Y. K. Lai, Charles R. Harrington, Claude M. Wischik (Corresponding Author)

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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.

Original languageEnglish
Article number19
Pages (from-to)1-19
Number of pages19
JournalBiomolecules
Volume6
Issue number2
DOIs
Publication statusPublished - 8 Apr 2016

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Phosphorylation
Pathology
Tubulin
Alzheimer Disease
Agglomeration
Tauopathies
tau Proteins
Prions
Substrates
Carrier Proteins
Polymers
Nucleation
Molecules
Pharmaceutical Preparations
Proteins

Keywords

  • Alzheimer’s disease
  • tau protein
  • phosphorylation
  • protein aggregation

Cite this

Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer's Disease. / Lai, Robert Y. K.; Harrington, Charles R.; Wischik, Claude M. (Corresponding Author).

In: Biomolecules, Vol. 6, No. 2, 19, 08.04.2016, p. 1-19.

Research output: Contribution to journalArticle

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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.",
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