Distinct microscopic mechanisms for the accelerated aggregation of pathogenic Tau mutants revealed by kinetic analysis.

08:00 EDT 24th March 2020 | BioPortfolio

Summary of "Distinct microscopic mechanisms for the accelerated aggregation of pathogenic Tau mutants revealed by kinetic analysis."

The self-assembly of Tau protein into amyloid structures is associated with Alzheimer's disease and other tauopathies. Dominant familial mutations in the Tau gene, such as P301L and P301S, increase the propensity of the Tau protein to aggregate abnormally into filaments. A quantitative description of the fibrillization process of Tau will facilitate the understanding of the cytotoxicity of Tau aggregates and their intercellular spreading. Here, we investigated the aggregation kinetics of Tau and disease-associated P301L and P301S mutants by combined thioflavin T assay and kinetic modeling, which revealed the rate constants of individual microscopic steps in the process of amyloid formation. Compared to WT Tau, P301L shows a larger primary nucleation rate while P301S has higher elongation and fragmentation rates and a more apparent fibril annealing process. Cross-seeding assays and FRET experiments indicate that the structures of the fibrillar nuclei of the three variants are distinct. These results provide detailed insights into how the amyloid aggregation mechanism of Tau protein is affected by the familial mutations P301L and P301S, and relates the physical properties of Tau mutants to their pathogenic mechanism.


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This article was published in the following journal.

Name: Physical chemistry chemical physics : PCCP
ISSN: 1463-9084


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