Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations
ABSTRACT α‐Synuclein (α‐syn) forms structurally distinct fibril polymorphs with various pathological activities in different subtypes of synucleinopathies, such as Parkinson's disease (PD). As a unique proteinaceous polymer, the mechanical property of α‐syn fibril is a primary determinant of it...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
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| Series: | Aggregate |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/agt2.70023 |
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| Summary: | ABSTRACT α‐Synuclein (α‐syn) forms structurally distinct fibril polymorphs with various pathological activities in different subtypes of synucleinopathies, such as Parkinson's disease (PD). As a unique proteinaceous polymer, the mechanical property of α‐syn fibril is a primary determinant of its neurotoxicity, immunogenicity, and seeding and transmission capacity. Nevertheless, how genetic mutations in α‐syn fibrils cause varied polymer behaviors remains largely unknown. Using optical tweezers, we quantitatively characterize the mechanical properties of three α‐syn fibril variants at the single‐molecule level. We find that wild‐type α‐syn fibrils are generally more sustainable to an axial disruption force than those formed by the disease‐causing E46K and A53T α‐syn mutants, whereas their heterogeneous elastic properties manifest similarity. Based on the molecular dynamics simulations, the β‐sheet motif and the interface between the two protofilaments dominate in stabilizing the fibril structure. Additionally, single‐molecule and simulation analysis consistently reveal the force‐driven α‐syn protein unfolding without a fibril break. Due to the flexible periphery, these subtle structural changes become more pronounced with the E46K fibril. The structure–mechanics relationship of α‐syn fibrils built in this work sheds new light on the fibril assembly and disassembly mechanism and the mutant‐associated pathogenesis in PD. |
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| ISSN: | 2692-4560 |