Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic...

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Parkinson's disease (PD) pathology involves α-synuclein aggregation into Lewy Bodies and Lewy Neurites.
• Mildly acidic intracellular environments, like endosomes, accelerate α-synuclein aggregation via secondary processes.
• Distinguishing between fibril surface nucleation and fragmentation is crucial for understanding PD pathogenesis.

Purpose of the Study:

• To differentiate between fibril surface nucleation and fragmentation as the dominant secondary mechanism in α-synuclein aggregation.
• To elucidate the molecular mechanisms driving accelerated protein aggregation in Parkinson's disease.

Main Methods:

• Differential sedimentation analysis
• Trap and seed experiments
• Quartz crystal microbalance (QCM) analysis
• Super-resolution microscopy

Main Results:

• Secondary nucleation of α-synuclein monomers on existing fibril surfaces was identified as the primary driver of new aggregate formation.
• Fibril fragmentation was found to contribute negligibly to the overall aggregation process.
• Newly formed oligomers efficiently elongate and act as templates for further secondary nucleation.

Conclusions:

• Secondary nucleation on fibril surfaces is the dominant mechanism responsible for rapid α-synuclein aggregate generation in PD.
• This mechanism has significant implications for understanding the cell-to-cell spreading of Parkinson's disease pathology.
• Targeting secondary nucleation may offer novel therapeutic strategies for Parkinson's disease.