Cryo-EM structures of tau filaments

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tauopathies are neurodegenerative diseases characterized by the aggregation of microtubule-associated protein tau (MAPT) into filamentous inclusions.
• Distinct cellular and neuroanatomical distributions of tau inclusions suggest disease-specific molecular conformers, analogous to prion strains.

Purpose of the Study:

• To elucidate the atomic structures of tau filaments in various human tauopathies.
• To understand the molecular basis of disease specificity in tauopathies.

Main Methods:

• Electron cryo-microscopy (cryo-EM) was employed to determine the high-resolution structures of tau filaments extracted directly from human brain tissue.
• Comparative structural analysis was performed across different tauopathies.

Main Results:

• Atomic structures of tau filaments revealed unique, disease-specific folds for each tauopathy studied.
• These tau filament folds were conserved among individuals with the same disease, indicating a consistent molecular pathology.
• In vitro tau aggregation experiments produced different structures compared to those observed in the brain.

Conclusions:

• Each human tauopathy is characterized by a distinct tau filament conformation.
• Factors such as tau isoform composition, post-translational modifications, and cofactors likely influence in vivo filament formation.
• Understanding these disease-specific tau structures is critical for deciphering the molecular mechanisms of tauopathies.