Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein (α-syn) misfolding and aggregation into Lewy bodies are hallmarks of Parkinson's disease (PD).
• Cell-to-cell transmission of α-syn pathology is linked to soluble amyloid oligomers preceding Lewy body formation.
• In vitro-generated oligomers can induce intracellular aggregation in cell models.

Purpose of the Study:

• To characterize a specific population of α-syn oligomers using ESI-ion mobility spectrometry (IMS)-MS.
• To compare the properties of these MS-compatible oligomers with those known for seeding and pore-forming capabilities.
• To investigate the structural and functional characteristics of α-syn oligomers related to pathology transmission.

Main Methods:

• Electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) for oligomer characterization.
• Comparison of MS-compatible oligomers with known toxic oligomer types.
• Analysis of epitope profiles and structural conformations (dimers to hexamers).

Main Results:

• MS-compatible α-syn oligomers were identified, ranging from dimers to hexamers.
• These oligomers demonstrated the ability to induce intracellular aggregation, similar to known toxic forms.
• Distinct epitope profiles correlated with toxic gain-of-function across different oligomer types.
• Higher-order oligomers exhibited compact, ring-like structures, while lower-order oligomers were more diverse and unstructured.

Conclusions:

• The characterized MS-compatible oligomers possess the capacity to induce intracellular aggregation and transmit pathology.
• The compact, ring-like structure of higher-order oligomers may facilitate cell-to-cell transfer and evade protease degradation.
• Understanding these structural features provides insights into the mechanism of α-syn pathology propagation in neurological disorders like PD.