9GG1

P301T type I tau filaments from human brain

Summary for 9GG1

• Entry DOI: 10.2210/pdb9gg1/pdb
• EMDB information: 51320
• Descriptor: Isoform Tau-D of Microtubule-associated protein tau (1 entity in total)
• Functional Keywords: p301t tau, frontotemporal dementia and parkinsonism linked to chromosome 17, electron cryo-microscopy, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 46161.21

Authors

Schweighauser, M.,Shi, Y.,Murzin, A.G.,Garringer, H.J.,Vidal, R.,Murrell, J.R.,Erro, M.E.,Seelaar, H.,Ferrer, I.,van Swieten, J.C.,Ghetti, B.,Scheres, S.H.W.,Goedert, M. (deposition date: 2024-08-12, release date: 2024-09-11)

Primary citation

Schweighauser, M.,Shi, Y.,Murzin, A.G.,Garringer, H.J.,Vidal, R.,Murrell, J.R.,Erro, M.E.,Seelaar, H.,Ferrer, I.,van Swieten, J.C.,Ghetti, B.,Scheres, S.H.W.,Goedert, M.
Novel tau filament folds in individuals with MAPT mutations P301L and P301T.
Biorxiv, 2024

PubMed Abstract: Mutations in , 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 variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common 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.

PubMed: 39185206
DOI: 10.1101/2024.08.15.608062

Experimental method

ELECTRON MICROSCOPY (2.26 Å)