Identification of the Tau phosphorylation pattern that drives its aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• The relationship between Tau protein phosphorylation and its aggregation into pathological fibers is complex.
• Multiple phosphorylation sites on Tau complicate the study of its aggregation mechanisms.
• Understanding Tau aggregation is crucial for neurodegenerative diseases like Alzheimer's.

Purpose of the Study:

• To elucidate the specific role of Tau phosphorylation sites in Tau fiber formation.
• To generate well-characterized phosphorylated Tau samples for detailed analysis.

Main Methods:

• In vitro kinase assays were employed to create specific Tau phosphorylation patterns.
• Nuclear Magnetic Resonance (NMR) spectroscopy was used for detailed structural analysis.
• Thioflavin T fluorescence and electron microscopy confirmed fiber formation.

Main Results:

• Combined phosphorylation at Ser202/Thr205/Ser208, with no phosphorylation at Ser262, induced rapid Tau fiber formation.
• Conformational analysis of phosphorylated peptides revealed a link between aggregation and destabilization of a specific turn-like structure.
• This destabilization is associated with phosphorylation at Ser202/Thr205.

Conclusions:

• Specific phosphorylation patterns on Tau, particularly at Ser202/Thr205/Ser208 and the absence of phosphorylation at Ser262, are critical drivers of Tau aggregation.
• The destabilization of a key structural motif by phosphorylation directly correlates with Tau's propensity to form fibers.
• These findings provide a refined molecular understanding of Tauopathies.