Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity
The aggregation of α-synuclein (α-syn) into amyloid fibrils is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The mechanisms underlying the structural transition of soluble and innocuous α-syn to aggregated neurotoxic forms remains largely unknown. The di...
| Authors: | , , , , , , , , , |
|---|---|
| Format: | article |
| Publication Date: | 2019 |
| Country: | España |
| Institution: | Universitat Autònoma de Barcelona |
| Repository: | Dipòsit Digital de Documents de la UAB |
| Language: | English |
| OAI Identifier: | oai:ddd.uab.cat:226349 |
| Online Access: | https://ddd.uab.cat/record/226349 https://dx.doi.org/urn:doi:10.1016/j.redox.2019.101135 |
| Access Level: | Open access |
| Keyword: | α-syn, α-synuclein PD, Parkinson's disease NAC, non-amyloid β-component α-synCC, disulfide bridge-containing variant CD, circular dichroism Th-T, Thioflavin-T CR, Congo Red TEM, Transmission electron microscopy PK, proteinase K DOPC, dioleoylphosphatidylcholine DMPS, dimyristoylphosphatidylserine α-synuclein Disulfide bond Amyloid Protein aggregation Parkinson's disease |
| Summary: | The aggregation of α-synuclein (α-syn) into amyloid fibrils is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The mechanisms underlying the structural transition of soluble and innocuous α-syn to aggregated neurotoxic forms remains largely unknown. The disordered nature of α-syn has hampered the use of structure-based protein engineering approaches to elucidate the molecular determinants of this transition. The recent 3D structure of a pathogenic α-syn fibril provides a template for this kind of studies. The structure supports the NAC domain being a critical element in fibril formation, since it constitutes the core of the fibril, delineating a Greek-key motif. Here, we stapled the ends of this motif with a designed disulfide bond and evaluated its impact on the conformation, aggregation and toxicity of α-syn in different environments. The new covalent link biases the native structural ensemble of α-syn toward compact conformations, reducing the population of fully unfolded species. This conformational bias results in a strongly reduced fibril formation propensity both in the absence and in the presence of lipids and impedes the formation of neurotoxic oligomers. Our study does not support the Greek-key motif being already imprinted in early α-syn assemblies, discarding it as a druggable interface to prevent the initiation of fibrillation. In contrast, it suggests the stabilization of native, compact ensembles as a potential therapeutic strategy to avoid the formation of toxic species and to target the early stages of PD. |
|---|