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Updated: Jun 15, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Novel tau filament folds in individuals with MAPT mutations P301L and P301T
Manuel Schweighauser1,2, Yang Shi1,3,2, Alexey G Murzin1,2
1MRC Laboratory of Molecular Biology, Cambridge, UK.
Abstract:
Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case 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. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.
Insights
Mutations in the microtubule-associated protein tau (MAPT) gene cause frontotemporal dementia. Cryo-EM structures reveal distinct tau folds in P301L and P301T mutations, suggesting unique inherited tauopathies.
Area of Science:
- Neuroscience
- Genetics
- Structural Biology
Background:
- Mutations in the microtubule-associated protein tau (MAPT) gene are linked to frontotemporal dementia and parkinsonism (FTDP-17).
- These mutations lead to the formation of filamentous tau inclusions within brain cells.
- Missense mutations at residue P301 are common in FTDP-17 and promote the assembly of mutant tau into filaments.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structures of tau filaments in individuals with P301L and P301T MAPT mutations.
- To characterize the structural differences and similarities of tau folds associated with these specific mutations.
- To investigate the implications of these structural findings for understanding inherited tauopathies.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the high-resolution structures of tau filaments.
- Filaments were isolated from brain tissue of individuals with P301L and P301T MAPT mutations.
- Structural analysis and comparison of the identified tau folds were performed.
Main Results:
- A novel three-lobed tau fold, similar to the Pick's disease tau fold, was observed in all P301L mutation cases.
- Two distinct tau folds were identified in the P301T mutation case: a variant of the three-lobed fold and a major V-shaped fold.
- The P301T major tau fold exhibited partial similarity to tau folds found in corticobasal degeneration and argyrophilic grain disease.
Conclusions:
- The distinct tau filament structures associated with P301L and P301T mutations suggest these should be classified as separate inherited tauopathies.
- The structural diversity highlights the complex mechanisms underlying tau aggregation in different MAPT mutations.
- Caution is advised when using model systems with these mutations to study sporadic tauopathies due to potential structural differences.
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