Elucidating Tau function and dysfunction in the era of cryo-EM

Area of Science:

• Neuroscience and Structural Biology
• Molecular mechanisms of neurodegenerative diseases

Background:

• Tau is a microtubule-associated protein essential for neuronal function.
• Pathological Tau forms fibrils, serving as hallmarks of tauopathies, including Alzheimer's disease (AD).
• Previous understanding of Tau's structure and function was limited before recent advancements.

Purpose of the Study:

• To review recent high-resolution cryo-electron microscopy (cryo-EM) findings on Tau protein structures.
• To contextualize new structural data within existing knowledge of Tau's physiology and pathology.
• To explore the link between Tau's structural insights and its functional and pathological roles in neurodegenerative diseases.

Main Methods:

• Comprehensive review of cryo-electron microscopy (cryo-EM) studies published in the last two years.
• Analysis of patient-derived Tau fibrils from Alzheimer's disease (AD), Pick's disease, and chronic traumatic encephalopathy (CTE).
• Integration of new structural data with historical functional and structural observations of Tau.

Main Results:

• Cryo-EM has provided unprecedented high-resolution structures of Tau in both physiological and pathological states.
• Structures of Tau fibrils from AD, Pick's disease, and CTE reveal distinct molecular conformations.
• These structures represent key molecular endpoints in the progression of tauopathies.

Conclusions:

• Recent Tau structures from cryo-EM necessitate a re-evaluation of databases linking Tau variants to dementia.
• Structural insights provide a foundation for understanding the relationship between Tau's function and its pathological aggregation.
• Integrating new structural data with prior knowledge is crucial for a comprehensive understanding of Tau's role in health and disease.