α-Synuclein Aggregation Intermediates form Fibril Polymorphs with Distinct Prion-like Properties.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Synucleinopathies, such as Parkinson's disease, involve alpha-synuclein (α-Syn) amyloid formation.
• The structural diversity and prion-like strain behavior of α-Syn amyloids are increasingly recognized but poorly understood.
• The mechanisms generating different α-Syn fibril polymorphs from the same precursor protein remain elusive.

Purpose of the Study:

• To investigate the structure-function relationship of distinct α-Syn fibril polymorphs.
• To elucidate how different α-Syn aggregation intermediates influence fibril structure and cellular activity.
• To understand the implications of conformational heterogeneity in α-Syn aggregation for prion-like behavior.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy.
• Mass spectrometry.
• Cellular assays assessing seeding, internalization, and cell-to-cell transfer of α-Syn aggregates.

Main Results:

• Two α-Syn polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), were characterized.
• HMFs possess a compact core structure, showing low seeding potency but efficient cellular internalization and transfer.
• PMFs, less structured, lack transcellular transfer but induce significant α-Syn pathology and aggresome formation.

Conclusions:

• Conformational heterogeneity during α-Syn aggregation generates distinct fibril polymorphs.
• These polymorphs exhibit differential cellular activities, including seeding, internalization, and cell-to-cell propagation.
• The findings highlight the potential for diverse, prion-like behaviors arising from α-Syn aggregation intermediates in synucleinopathies.