Conformational Switch in the Alpha-Synuclein C-Terminal Domain Directs Its Fibril Polymorphs

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein (αSyn) inclusions are key pathological markers in synucleinopathies.
• Distinct αSyn fibril polymorphs are observed, but the mechanisms controlling their formation are unclear.

Purpose of the Study:

• To investigate the molecular determinants of αSyn fibril polymorphism.
• To identify the role of monomeric αSyn conformation in fibril morphology.

Main Methods:

• Systematic variation of ionic strength and temperature to induce fibril formation.
• Solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy to analyze fibril structure.
• Investigation of C-terminal domain conformational changes.

Main Results:

• Two distinct αSyn polymorphs (twisted and rod-like) were generated by altering ionic strength and temperature.
• Both polymorphs share a conserved core structure, with differences at protofilament interfaces.
• A specific C-terminal conformational change in monomeric αSyn acts as a molecular switch for polymorphism.
• Calcium binding to the C-terminus can trigger this conformational switch.

Conclusions:

• Monomeric αSyn conformation, particularly in the C-terminal domain, dictates fibril morphology.
• Environmental factors, such as calcium, can influence αSyn fibrogenesis by modulating C-terminal conformation.
• These findings offer insights into the structural basis of synucleinopathies and potential therapeutic targets.