Polyphosphate Initiates Tau Aggregation through Intra- and Intermolecular Scaffolding

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tau aggregation and deposition are key features of tauopathies.
• The precise cellular and molecular triggers for tau aggregation remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms by which cytoplasmic polyphosphates (polyP) initiate tau aggregation.
• To elucidate the role of polyP chain length in tau conformational changes and aggregation.

Main Methods:

• Studied conformational changes in full-length tau using biophysical techniques.
• Investigated polyP binding sites within tau, focusing on proline-rich and microtubule-binding regions.
• Assessed the impact of polyP chain length on tau aggregation.

Main Results:

• PolyP induces conformational changes in tau, including compaction of specific regions and altered inter-domain interactions.
• The proline-rich region of tau is essential for polyP-induced compaction of the microtubule-binding region.
• Tau aggregation and the extent of conformational change are dependent on polyP chain length, with longer chains being more potent.

Conclusions:

• PolyP acts as a physiological inducer of tau aggregation through two primary mechanisms: altering tau conformation and cross-linking tau monomers.
• Understanding these initial steps is crucial for developing therapeutic strategies against tauopathies.