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Abstract
The crucial role of the neuronal Tau protein in microtubule stabilization and axonal transport suggests that too little or too much Tau might lead to neuronal dysfunction. The presence of a hyper-phosphorylated but non-aggregated molecule as a toxic species that might sequester normal Tau is discussed. We present recent in vitro results that might allow to dissect the role of individual phosphorylation sites on its structure and function. We also discuss in this review the role of phosphorylation for the aggregation of the neuronal Tau protein, and compare it to the aggregation induced by external poly-anions.
Acknowledgments
Alain Sillen was funded by a European Training and Mobility Grant (HPRN CT 2002 00241). Part of this work was funded by the Agence National de la Recherche Grant ANR 05 BLANC 0320 01 to Guy Lippens. Nathalie Sibille was funded by a fellowship of the AIRMA (Association internationale de recherche contre la maladie d'Alzheimer). The 600 MHz facility used in this study was funded by the Région Nord Pas de Calais (France), the CNRS, and the Institut Pasteur de Lille. The 800MHz spectrometer was funded within the French National project “NMR et Radiocristallographie structurale - Grand Bassin Parisien” by the Région Nord Pas de Calais (FEDER), CNRS, USTL and Research Ministry.
Figures and Tables
Figure 1 (Left) NMR assignment of the phosphorylation pattern of Tau after incubation with PKACitation14. (Right) Effect of a single phosphorylation event at Ser214 on the microtubule binding propertiesCitation15 (right, top) or on its tubulin polymerizing capacity (right, bottom). In both panes, the upper curve is Tau, and the lower one pSer214 Tau. The affinity of acrylodan labeled Tau towards taxol stabilzed microtubules was measured by FRET for Tau (solid curve) or pSer214 Tau (dotted line), whereas turbidity was used to evaluate the polymerization of tubulin into microtubules.
Figure 2 (Left) Electron microscopy picture of a Tau PHF promoted by incubation with heparin. (Right) Model for the amyloid core of the fiber, with heparin providing for the negative charges essential to compensate for the positive stretch formed by parallel in register stacking of lysine containing peptides.Citation33
