Distribution of Amyloid-Like and Oligomeric Species from Protein Aggregation Kinetics

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.National Ataxia Foundation, USA; 2) FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI‐01‐0145‐FEDER‐007274); 3) Project Norte‐01‐0145‐FEDER‐000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER); and 4) Project UID/EQU/00511/2013‐LEPABE (Laboratory for Process Engineering, Environment, Biotechnology and Energy—EQU/00511) by FEDER funds through Programa Operacional Competitividade e Internacionalização—COMPETE2020. P.T. thanks Ministerio de Economía y Competitividad (MINECO) and FEDER for research project MAT 2016‐80266‐R and Xunta de Galicia for grant GPC2015‐007. We thank Pedro J. B. Pereira for critical reading of the manuscript and Rui Fernandes for support with electron microscopy imagin