Distinct growth regimes of α-synuclein amyloid elongation

Horvath, Istvan,1979Chalmers tekniska högskola,Chalmers University of Technology (författare)

Addition of amyloid seeds to aggregation-prone monomers allows for amyloid fiber growth (elongation) omitting slow nucleation. We here combine Thioflavin T fluorescence (probing formation of amyloids) and solution-state NMR spectroscopy (probing disappearance of monomers) to assess elongation kinetics of the amyloidogenic protein, α-synuclein, for which aggregation is linked to Parkinson's disease. We found that both spectroscopic detection methods give similar kinetic results, which can be fitted by applying double exponential decay functions. When the origin of the two-phase behavior was analyzed by mathematical modeling, parallel paths as well as stop-and-go behavior were excluded as possible explanations. Instead, supported by previous theory, the experimental elongation data reveal distinct kinetic regimes that depend on instantaneous monomer concentration. At low monomer concentrations (toward end of experiments), amyloid growth is limited by conformational changes resulting in β-strand alignments. At the higher monomer concentrations (initial time points of experiments), growth occurs rapidly by incorporating monomers that have not successfully completed the conformational search. The presence of a fast disordered elongation regime at high monomer concentrations agrees with coarse-grained simulations and theory but has not been detected experimentally before. Our results may be related to the wide range of amyloid folds observed.

Welte, HannahUniversität Konstanz,University of Konstanz (författare)
Schmit, Jeremy D.Kansas State University (författare)
Kovermann, M.Universität Konstanz,University of Konstanz (författare)
Wittung Stafshede, Pernilla,1968Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)perwit (författare)
Chalmers tekniska högskolaUniversität Konstanz (creator_code:org_t)

Av författaren/redakt...: Horvath, Istvan, ...; Welte, Hannah; Schmit, Jeremy D ...; Kovermann, M.; Wittung Stafshed ...

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