Structure-based classification of tauopathies

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tauopathies are neurodegenerative diseases characterized by the aggregation of tau protein into filaments.
• Distinct tau filament structures have been previously identified in Alzheimer's disease, Pick's disease, CTE, and CBD.

Purpose of the Study:

• To elucidate the structural diversity of tau filaments in various tauopathies.
• To establish a hierarchical classification of tauopathies based on tau filament structures.

Main Methods:

• Cryo-electron microscopy was employed to determine the high-resolution structures of tau filaments from diverse tauopathy cases.
• Comparative structural analysis was performed to identify similarities and differences in tau filament folds.

Main Results:

• A novel three-layered tau filament fold was identified in progressive supranuclear palsy (PSP).
• Globular glial tauopathy shares similar tau filament structures with PSP.
• Argyrophilic grain disease (AGD) exhibits a distinct four-layered fold, similar to corticobasal degeneration, and is also found in aging-related tau astrogliopathy.
• MAPT gene mutations associated with AGD suggest a link between tau overproduction and the AGD fold.
• Familial British and Danish dementias share tau filament structures with Alzheimer's disease and primary age-related tauopathy.

Conclusions:

• The structural classification of tau filaments provides a new framework for understanding tauopathies.
• This classification complements existing diagnostic and neuropathological methods.
• The study identified intermediate filament structures in a PSP case, suggesting a potential new tauopathy entity.