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Distribution of Amyloid‐Like and Oligomeric Species from Protein Aggregation Kinetics
Author(s) -
Silva Alexandra,
Almeida Bruno,
Fraga Joana S.,
Taboada Pablo,
Martins Pedro M.,
MacedoRibeiro Sandra
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201707345
Subject(s) - fibril , amyloid fibril , amyloid (mycology) , protein aggregation , neurodegeneration , biophysics , kinetics , protein folding , nucleation , chemistry , amyloid β , biochemistry , biology , disease , medicine , physics , inorganic chemistry , organic chemistry , pathology , quantum mechanics
Amyloid fibrils and soluble oligomers are two types of protein aggregates associated with neurodegeneration. Classic therapeutic strategies try to prevent the nucleation and spread of amyloid fibrils, whilst diffusible oligomers have emerged as promising drug targets affecting downstream pathogenic processes. We developed a generic protein aggregation model and validate it against measured compositions of fibrillar and non‐fibrillar assemblies of ataxin‐3, a protein implicated in Machado–Joseph disease. The derived analytic rate‐law equations can be used to 1) identify the presence of parallel aggregation pathways and 2) estimate the critical sizes of amyloid fibrils. The discretized population balance supporting our model is the first to quantitatively fit time‐resolved measurements of size and composition of both amyloid‐like and oligomeric species. The new theoretical framework can be used to screen a new class of drugs specifically targeting toxic oligomers.