Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity

Anita Carija, Francisca Pinheiro, Jordi Pujols, Inês C. Brás, Diana Fernandes Lázaro, Carlo Santambrogio, Rita Grandori, Tiago F. Outeiro, Susanna Navarro, Salvador Ventura

Research output: Contribution to journalArticleResearch

16 Citations (Scopus)

Abstract

© 2019 The Authors 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.
Original languageEnglish
Article number101135
JournalRedox Biology
Volume22
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Amyloid
  • Disulfide bond
  • Parkinson's disease
  • Protein aggregation
  • α-synuclein

Fingerprint

Dive into the research topics of 'Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity'. Together they form a unique fingerprint.

Cite this