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Updated: May 3, 2026
In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening
Published on: November 20, 2018
Single mutations in tau modulate the populations of fibril conformers through seed selection
Virginia Meyer1, Paul D Dinkel, Yin Luo
1Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208 (USA).
Abstract:
Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer's disease and other neurodegenerative disorders. Self-assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron-electron resonance spectroscopy was used to investigate the conformational ensemble of four-repeat tau fibrils. Single point mutations at key positions in the protein (ΔK280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template-assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation.
Insights
Tau protein misfolding into fibrils drives Alzheimer's disease. Specific mutations alter tau fibril shapes, influencing disease progression and highlighting conformational compatibility in tau pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Tau protein aggregation into fibrils is a hallmark of Alzheimer's disease and other neurodegenerative conditions.
- The self-assembly of tau into fibrils is primarily driven by its microtubule-binding repeats, with variations in repeat number (three or four) between protein isoforms.
Purpose of the Study:
- To investigate the conformational ensemble of four-repeat tau fibrils using double electron-electron resonance (DEER) spectroscopy.
- To understand how specific point mutations affect the distribution of tau fibril conformers during template-assisted growth.
Main Methods:
- Utilized double electron-electron resonance (DEER) spectroscopy to probe the structure of tau fibrils.
- Introduced single point mutations into the four-repeat tau protein to assess their impact on fibril formation.
Main Results:
- Specific mutations (ΔK280, P301S, P312I, D314I) significantly altered the distribution of tau fibril conformers.
- Other mutations (I308M, S320F, G323I, G326I, Q336R) had no discernible effect on the fibril conformational ensemble.
- Demonstrated that mutations can influence seed selection in tau disease mutants.
Conclusions:
- Conformational compatibility plays a crucial role in the propagation of tau fibrils.
- These findings offer novel insights into the mechanisms of tau seed selection and fibril formation in neurodegenerative diseases.
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