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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Distinct tau filament folds in human MAPT mutants P301L and P301T
Manuel Schweighauser1, Yang Shi1,2, Alexey G Murzin1
1Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK.
Abstract:
Mutations in MAPT, the tau gene, give rise to frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with abundant filamentous tau inclusions in brain cells. Mutations that encode missense variants of residue P301 are the most common and result in the formation of filamentous inclusions made of mutant four-repeat tau. Here we report the cryo-electron microscopy structures of tau filaments from five individuals belonging to three different families with mutation P301L and from one individual from a family with mutation P301T. A distinct three-lobed tau fold resembling the two-layered fold of Pick's disease was present in the individuals with P301L tau. Two different tau folds were found in the individual with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease.
Insights
Mutations in the tau gene (MAPT) cause frontotemporal dementia and parkinsonism (FTDP-17). Cryo-EM revealed distinct tau filament structures associated with P301L and P301T mutations, offering insights into disease mechanisms.
Area of Science:
- Neuroscience
- Structural Biology
- Genetics
Background:
- Mutations in the MAPT gene, encoding tau protein, are linked to frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
- Missense variants at residue P301 are common, leading to filamentous inclusions of mutant four-repeat tau.
- Understanding the structural basis of these tau inclusions is crucial for elucidating disease pathogenesis.
Purpose of the Study:
- To determine the high-resolution structures of tau filaments from individuals with specific MAPT mutations (P301L and P301T).
- To characterize the distinct tau folds formed by these mutations and compare them to known tauopathies.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to visualize tau filaments.
- Structural analysis was performed on tau filaments isolated from individuals with P301L and P301T mutations.
Main Results:
- Distinct three-lobed tau folds were observed in individuals with the P301L mutation, resembling the fold in Pick's disease.
- Two tau folds were identified in the individual with the P301T mutation: a major V-shaped fold and a minor variant of the three-lobed fold.
- The P301T V-shaped fold showed partial similarity to tau folds found in corticobasal degeneration and argyrophilic grain disease.
Conclusions:
- Specific MAPT mutations (P301L and P301T) induce unique tau filament structures.
- These distinct tau folds may contribute to the differential pathologies observed in FTDP-17 and other tauopathies.
- The structural findings provide a molecular basis for understanding tau aggregation in neurodegenerative diseases.
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