Acetylation discriminates disease-specific tau deposition.

Area of Science:

• Neuroscience
• Protein Biochemistry
• Molecular Biology

Background:

• Pathogenic tau protein aggregation is a key feature of Alzheimer's disease and other tauopathies.
• The mechanisms governing tau isoform-specific aggregation remain poorly understood.

Purpose of the Study:

• To investigate the role of tau acetylation in isoform-specific aggregation.
• To identify specific acetylation sites that regulate tau aggregation.

Main Methods:

• Biochemical assays to assess tau aggregation.
• Site-directed mutagenesis to study acetylation.
• Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy to analyze tau fibril structure.

Main Results:

• Acetylation differentially affects tau aggregation: it inhibits four-repeat tau but promotes three-repeat tau amyloid formation.
• Acetylation of lysine 298 was identified as a critical site for isoform-specific aggregation.
• Structural analysis revealed distinct amyloid fibril structures for unmodified and acetylated three-repeat tau.

Conclusions:

• Acetylation acts as a crucial regulator of tau isoform selectivity in aggregation.
• Site-specific acetylation modulates tau structure, influencing the development of tauopathies.