Probing the Occurrence of Soluble Oligomers through Amyloid Aggregation Scaling Laws
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Title: | Probing the Occurrence of Soluble Oligomers through Amyloid Aggregation Scaling Laws |
Author: | Silva, Alexandra Sárkány, Zsuzsa Fraga, Joana S. Taboada Antelo, Pablo Ribeiro, Sandra Macedo Martins, Pedro M. |
Affiliation: | Universidade de Santiago de Compostela. Departamento de Física de Partículas |
Subject: | Protein aggregation | Amyloid | Soluble oligomers | Kinetic analysis | Nucleation | |
Date of Issue: | 2018 |
Publisher: | MDPI |
Citation: | Silva, A.; Sárkány, Z.; Fraga, J.S.; Taboada, P.; Macedo-Ribeiro, S.; Martins, P.M. Probing the Occurrence of Soluble Oligomers through Amyloid Aggregation Scaling Laws. Biomolecules 2018, 8, 108 |
Abstract: | Drug discovery frequently relies on the kinetic analysis of physicochemical reactions that are at the origin of the disease state. Amyloid fibril formation has been extensively investigated in relation to prevalent and rare neurodegenerative diseases, but thus far no therapeutic solution has directly arisen from this knowledge. Other aggregation pathways producing smaller, hard-to-detect soluble oligomers are increasingly appointed as the main reason for cell toxicity and cell-to-cell transmissibility. Here we show that amyloid fibrillation kinetics can be used to unveil the protein oligomerization state. This is illustrated for human insulin and ataxin-3, two model proteins for which the amyloidogenic and oligomeric pathways are well characterized. Aggregation curves measured by the standard thioflavin-T (ThT) fluorescence assay are shown to reflect the relative composition of protein monomers and soluble oligomers measured by nuclear magnetic resonance (NMR) for human insulin, and by dynamic light scattering (DLS) for ataxin-3. Unconventional scaling laws of kinetic measurables were explained using a single set of model parameters consisting of two rate constants, and in the case of ataxin-3, an additional order-of-reaction. The same fitted parameters were used in a discretized population balance that adequately describes time-course measurements of fibril size distributions. Our results provide the opportunity to study oligomeric targets using simple, high-throughput compatible, biophysical assays. |
Publisher version: | https://doi.org/10.3390/biom8040108 |
URI: | http://hdl.handle.net/10347/22804 |
DOI: | 10.3390/biom8040108 |
E-ISSN: | 2218-273X |
Rights: | © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) |
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Except where otherwise noted, this item's license is described as © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)