C-Terminal Truncated α-Synuclein Fibrils Contain Strongly Twisted β-Sheets

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• C-terminal truncations of wild-type alpha-synuclein (WT-αS) enhance amyloid aggregation in vitro and in vivo.
• These truncations are linked to accelerated Parkinson's disease (PD) progression, potentially due to altered fibril polymorph formation.

Purpose of the Study:

• To investigate how C-terminal truncations of αS influence the structure and morphology of amyloid fibrils.
• To understand the structural basis for distinct pathologies associated with different αS fibril polymorphs.

Main Methods:

• High-resolution microscopy
• Advanced vibrational spectroscopy (1D-IR, 2D-IR, vibrational circular dichroism)
• Circular dichroism spectroscopy

Main Results:

• The C-terminal truncation variant (1-108-αS) forms amyloid fibrils with unique structure and morphology.
• 1-108-αS fibrils exhibit a distinct negative circular dichroism band at ~230 nm, unlike the canonical ~218 nm band.
• These fibrils possess strongly twisted β-sheets with increased inter-β-sheet distance and higher solvent exposure compared to WT-αS fibrils.
• 1-108-αS fibrils resist the incorporation of WT-αS monomers due to their distinct β-sheet structure.

Conclusions:

• C-terminal truncation significantly alters αS fibril organization, leading to unique structural and morphological characteristics.
• The distinct structure of 1-108-αS fibrils may contribute to differential PD pathologies.
• The resistance of these fibrils to monomer incorporation highlights a novel mechanism potentially influencing disease progression.