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

TY - JOUR

T1 - Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer's Disease

AU - Lai, Robert Y. K.

AU - Harrington, Charles R.

AU - Wischik, Claude M.

N1 - Acknowledgments: Depolymerised bovine tubulin was kindly donated by J. Kilmartin (MRC Laboratory of Molecular Biology, Cambridge). This work was supported by the Medical Research Council (UK), a Wellcome Trust Studentship to RL, the Leopold Muller Estate, and the Newton Trust (Trinity College, Cambridge). We gratefully acknowledge Academic Books for permission to use Table 2 and Figures 2–4 which correspond to Table 1 and Figures 20–22 from Wischik C.M., Lai, R.Y.K. and Harrington, C.R. Modelling prion-like processing of tau protein in Alzheimer’s disease for pharmaceutical development, in Brain Microtubule Associated Proteins: Modifications in Disease, Avila, J.; Brandt, R.; Kosik, K.S., Eds. Harwood Academic Publishers: Amsterdam, The Netherlands, 1997. Erratum published on 12 August 2016, see Biomolecules 2016, 6(3), 35. http://www.mdpi.com/2218-273X/6/3/35

PY - 2016/4/8

Y1 - 2016/4/8

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - tau protein

KW - phosphorylation

KW - protein aggregation

U2 - 10.3390/biom6020019

DO - 10.3390/biom6020019

M3 - Article

VL - 6

SP - 1

EP - 19

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 2

M1 - 19

ER -