Water-Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Hyperphosphorylation of tau protein is a key feature of tauopathies, neurodegenerative diseases characterized by tau aggregation.
• The precise role of tau phosphorylation in driving fibril formation and stability remains incompletely understood.
• Conventional models suggest electrostatic repulsion between closely packed phosphoryl groups would destabilize fibrils.

Purpose of the Study:

• To investigate the hypothesis that phosphoryl groups within tau amyloid fibrils form stabilizing structures.
• To elucidate the molecular mechanism by which tau phosphorylation influences fibril assembly and stability.
• To explore the potential of these structures as targets for therapeutic interventions.

Main Methods:

• Utilized seeding-competent tau peptide fibrils (jR2R3-P301L) with specific phosphorylation sites (S305p, Y310p).
• Employed multiple-quantum spin counting (MQ-SC) with 31P solid-state NMR and dynamic nuclear polarization (DNP) to detect phosphorus arrangements.
• Performed molecular dynamics simulations and 2D 1H-31P heteronuclear correlation NMR to confirm structural interactions.

Main Results:

• Detected at least six linearly arranged phosphorus spins within protofibrils, consistent with a high MQ coherence order.
• Molecular dynamics simulations revealed water-mediated geometries for phosphoryl wires.
• NMR experiments confirmed water-bridged phosphoryl-phosphoryl contacts, and S305 phosphorylation enhanced fibril stability.

Conclusions:

• Tau phosphorylation within the fibril core promotes fibril registry and stability via water-mediated, hydrogen-bonded phosphoryl wires.
• This mechanism offers a new perspective on tau aggregation in tauopathies.
• These phosphoryl wires may represent a structural signature for developing novel tau-targeting therapeutics.