Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in α-Synuclein Fibrils

Area of Science:

• Neurodegenerative disease research
• Structural biology
• Biochemistry

Background:

• Synucleinopathies, like Parkinson's disease, are characterized by alpha-Synuclein aggregation.
• Cryo-EM revealed a mysterious core density in alpha-Synuclein fibrils, hypothesized to be negatively charged.
• Polyphosphate (polyP) is known to accelerate alpha-Synuclein fibril formation.

Approach:

• Utilized blind docking and molecular dynamics simulations to model polyP binding sites in alpha-Synuclein fibrils.
• Performed in vitro and cellular experiments to validate the role of specific lysine residues (K43, K45).

Key Points:

• PolyP models consistently placed it within a lysine-rich pocket coordinating the mystery density in patient-derived fibrils.
• Mutating key lysine residues (K43, K45) abolished polyP's effects on alpha-Synuclein aggregation, conformation, stability, and cytotoxicity.
• PolyP likely neutralizes charge repulsion between lysine residues, facilitating alpha-Synuclein aggregation.

Conclusions:

• PolyP fits the unidentified electron density in in vivo alpha-Synuclein fibrils.
• PolyP plays a critical role in the structural and functional changes of alpha-Synuclein relevant to synucleinopathies.