Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein

By N. Cremades, Samuel I. A. Cohen, E. Deas, A. Abramov, A. Chen, Á. Orte, Massimo Sandal, Richard W. Clarke, Paul D. Dunne, F. Aprile and 5 more. Cell, 2012

885 citations recorded by the source corpus.

Summary Here, we use single-molecule techniques to study the aggregation of α-synuclein, the protein whose misfolding and deposition is associated with Parkinson's disease. We identify a conformational change from the initially formed oligomers to stable, more compact proteinase-K-resistant oligomers as the key step that leads ultimately to fibril formation. The oligomers formed as a result of the structural conversion generate much higher levels of oxidative stress in rat primary neurons than do the oligomers formed initially, showing that they are more damaging to cells. The structural conversion is remarkably slow, indicating a high kinetic barrier for the conversion and suggesting that there is a significant period of time for the cellular protective machinery to operate and potentially for therapeutic intervention, prior to the onset of cellular damage. In the absence of added soluble protein, the assembly process is reversed and fibrils disaggregate to form stable oligomers, hence acting as a source of cytotoxic species.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/f00a7f1ff062976c5c8078e0abae0beb978ae8af

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Citations in the corpus

Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation (2014, background): “In addition, mechanical action, such as shaking and stirring, is often used to accelerate the aggregation of α-synuclein (32).”
Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism (2013, background): “(2005) 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils.”
Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “252 Though this structural turnover is remarkedly slow due to the kinetic barrier, the reaction speed would sharply increase with enhanced aggregation, formation of β sheet oligomers, and dysregulation of compensatory mechanisms.”
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The amyloid state and its association with protein misfolding diseases (2014, background): “Paired betasheet structure of an Aβ(1-40) amyloid fibril revealed by electron microscopy.”