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Thermodynamic characterization of amyloid polymorphism by microfluidic transient incomplete separation
Azad Farzadfard1,2, Antonin Kunka1, Thomas Oliver Mason1
1Protein Biophysics Group, Department of Biotechnology and Biomedicine, Technical University of Denmark Søltofts Plads, Building 227, Kgs. Lyngby 2800 Denmark alebu@dtu.dk.
Chemical Science
|February 16, 2024
Summary
This study introduces a novel microfluidic method to measure amyloid fibril stability, revealing that fibril formation can be kinetically or thermodynamically controlled. This work quantifies differences in stability between alpha-synuclein fibril polymorphs.
Area of Science:
- Biochemistry
- Biophysics
- Neuroscience
Background:
- Amyloid fibrils, like those of alpha-synuclein, are implicated in neurodegenerative diseases.
- Research has primarily focused on amyloid formation kinetics, with less attention to thermodynamic stability.
- Understanding fibril stability is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To develop and apply a novel method for quantifying amyloid fibril thermodynamic stability.
- To investigate and compare the thermodynamic stability of different alpha-synuclein fibril polymorphs.
- To determine whether fibril formation is under kinetic or thermodynamic control.
Main Methods:
- Utilized transient incomplete separation of species in laminar flow within a microfluidic capillary.
- Employed chemical depolymerization to quantify equilibrium concentrations of fibrils and monomers.
- Separated species based on differential diffusivity for label-free, sample-economical analysis.
Main Results:
- Quantified the thermodynamic stability of alpha-synuclein fibril polymorphs for the first time.
- Demonstrated that amyloid fibril formation can be governed by either kinetic or thermodynamic factors.
- Showed that solution conditions can modulate amyloid fibril stability, causing both stabilization and destabilization.
Conclusions:
- Established thermodynamic stability as a critical parameter for understanding amyloid fibril polymorphism.
- Highlighted the importance of considering thermodynamic control in fibril formation.
- Provided a new, widely applicable method for assessing fibril stability in neurodegenerative disease research.
