Structural remodeling during amyloidogenesis of physiological Nα-acetylated α-synuclein

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Parkinson's disease is characterized by alpha-synuclein (AS) misfolding and aggregation into amyloid fibrils.
• Soluble AS oligomers are implicated as cytotoxic intermediates in neurodegeneration.
• The physiological form of AS is N-terminally acetylated (Ac-AS).

Purpose of the Study:

• To investigate the structural reorganization during N-terminally acetylated alpha-synuclein (Ac-AS) fibrillogenesis.
• To compare the biophysical properties of Ac-AS conformational ensembles with non-acetylated AS.
• To elucidate the role of transient intermediates in Ac-AS amyloid formation.

Main Methods:

• Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy was employed to monitor structural changes.
• Characterization of Ac-AS monomers, oligomers, and fibrils.
• Analysis of biophysical properties including hydrodynamic, tinctorial, structural, and membrane-leakage characteristics.

Main Results:

• Ac-AS monomers, oligomers, and fibrils exhibit similar biophysical properties to non-acetylated AS.
• ATR-FTIR revealed the formation of antiparallel beta-sheet structures as early intermediates during Ac-AS aggregation.
• These antiparallel intermediates transition into parallel beta-sheet fibrils, with helix-rich/disordered species involved in the process.

Conclusions:

• Ac-AS aggregation proceeds through distinct structural intermediates, including antiparallel beta-sheet assemblies.
• Understanding these conformational changes provides insights into the mechanism of AS amyloid formation in Parkinson's disease.
• The study highlights the importance of N-terminal acetylation in AS structural dynamics.