Dopamine-Induced Tau Modification Prevents Pathological Phosphorylation and Generates a Distinct Fibril Polymorph

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tau aggregation is central to tauopathies, including Alzheimer's disease.
• Dopamine modification of tau has been identified as protective, but its mechanisms are unclear.

Purpose of the Study:

• To elucidate the structural and functional consequences of dopamine modification on tau protein.
• To investigate how dopamination affects tau phosphorylation, fibrillization, and structure.

Main Methods:

• Solution Nuclear Magnetic Resonance (NMR) spectroscopy
• In vitro fibrillization assays
• Cellular seeding assays
• Cryo-electron microscopy (cryo-EM)

Main Results:

• Dopamine modification at Cys322 suppressed pathogenic tau phosphorylation.
• Dopaminated tau showed reduced in vitro fibrillization and cellular seeding activity.
• Cryo-EM revealed a unique tau fibril polymorph with a minimal core structure.

Conclusions:

• Dopamine modification protects against tau pathology by altering tau structure and reducing aggregation.
• Atomic-level insights into post-translational modifications of tau are crucial for understanding tauopathies.