Specific phosphorylation patterns control the interplay between aggregation and condensation of Tau-R4 peptides

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Protein phosphorylation regulates protein activity and self-assembly.
• Aberrant Tau self-assembly into aggregates and condensates is central to Tauopathies like Alzheimer's Disease.

Purpose of the Study:

• To investigate how specific phosphorylation patterns regulate Tau self-assembly.
• To understand the interplay between Tau aggregation and condensation at a residue level.
• To introduce a peptide-based approach for analyzing phosphorylation patterns.

Main Methods:

• Utilized a peptide-based approach for systematic analysis of phosphorylation patterns.
• Synthesized multi-phosphorylated peptides from the Tau R4 domain using advanced methods.
• Analyzed the impact of specific phosphorylations on Tau aggregation and condensation.

Main Results:

• Phosphorylation at Ser341 promotes Tau aggregation.
• Phosphorylation at Ser352 enhances Tau condensation.
• Phosphorylation at Ser356 inhibits both aggregation and condensation.
• Distinct microenvironments around phosphorylation sites dictate outcomes.

Conclusions:

• Specific phosphorylation patterns precisely control Tau self-assembly, differentiating between aggregation and condensation.
• The peptide-based method provides residue-level resolution, complementing protein-level studies.
• Findings offer mechanistic insights into Tauopathies and potential therapeutic targets.