Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide
| Autor: | Christopher M. Dobson, Paolo Arosio, Sara Linse, Georg Meisl, Michele Vendruscolo, Katja Bernfur, Andela Saric, Thomas C. T. Michaels, Samo Curk, Alexander J. Dear, Samuel I. A. Cohen, Tuomas P. J. Knowles |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Peptide 010402 general chemistry Amyloid fibril Fibril 01 natural sciences Oligomer 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound Protein Misfolding Diseases Monomer chemistry Biophysics 030304 developmental biology |
| DOI: | 10.1101/2020.01.08.897488 |
| Popis: | Oligomeric aggregates populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach combining theory, experiment, and simulation, we reveal in molecular detail the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we find that most Aβ42 oligomers dissociate to their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar species. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases. |
| Databáze: | OpenAIRE |
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