Differential Membrane Binding and Seeding of Distinct α-Synuclein Fibrillar Polymorphs

Area of Science:

• Neuroscience
• Molecular Biology
• Protein Aggregation

Background:

• Alpha-synuclein (α-Syn) aggregation causes synucleinopathies like Parkinson's disease and multiple system atrophy.
• Structurally distinct α-Syn fibril polymorphs have been shown to trigger different disease hallmarks in vivo.
• Understanding the structural-molecular basis of these differences is crucial for disease mechanism insights.

Purpose of the Study:

• To establish the structural-molecular basis for how distinct α-Syn polymorphs differentially affect neuronal function.
• To investigate the differential binding and clustering of α-Syn polymorphs at the neuronal plasma membrane.
• To explore the impact of α-Syn polymorphs on synaptic protein redistribution and neuronal network activity.

Main Methods:

• Utilized primary neuronal cultures and organotypic hippocampal slice cultures from wild-type mice.
• Investigated the binding and clustering of distinct α-Syn polymorphs at the plasma membrane.
• Analyzed the polymorph-dependent synaptic redistribution of specific ion channels and receptors (e.g., α3-Na+/K+-ATPase, GluA2, GluN2B).
• Measured alterations in neuronal network activity following seeded α-Syn aggregation.

Main Results:

• Demonstrated that distinct α-Syn fibril polymorphs exhibit differential binding and clustering at the neuronal plasma membrane.
• Showed polymorph-dependent and concentration-dependent seeding of α-Syn aggregation.
• Revealed a polymorph-dependent redistribution of synaptic proteins, including specific glutamate receptors and ion transporters.
• Observed polymorph-dependent alterations in neuronal network activity.

Conclusions:

• Distinct α-Syn polymorphs interact differently with neuronal membranes, providing a structural-molecular basis for synucleinopathy variations.
• These differential interactions lead to specific synaptic protein redistribution and altered neuronal network function.
• Findings offer new insights into how α-Syn polymorphs induce neuronal dysfunction and contribute to distinct disease pathologies.