The Pick fold in tau filaments from human MAPT mutants

By
Chao Qi
Sofia Lövestam
Jenny Shi
Alexey G. Murzin
Sew Peak-Chew
Thomas T. Warner
Harro Seelaar
Patrick W. Cullinane
Zane Jaunmuktane
John C. van Swieten
Sjors H. W. Scheres
Michel Goedert
July 8, 2026
0 min

Acta Neuropathologica

Background

Tauopathies, including frontotemporal dementia and Pick's disease, are characterized by the aggregation of tau protein into filamentous structures. Understanding the structural variations of tau filaments associated with specific MAPT mutations is crucial for elucidating the pathogenesis of these neurodegenerative disorders.

Data Highlights

Mutation	Filament Structure	Resolution (Å)
D252V	Pick fold	2.8
ΔG389-I392	Pick fold	2.3
G272V	Open Pick fold	N/A
S320F	Open Pick fold	N/A

Key Findings

MAPT mutations D252V and ΔG389-I392 produce tau filaments with the Pick fold.
G272V and S320F mutations result in a more open variant of the Pick fold.
Filaments from individuals with familial frontotemporal dementia show abundant 3R tau-immunoreactive Pick bodies.
Western blotting reveals specific tau banding patterns associated with different mutations.
Structural analysis aids in understanding the relationship between tau filament morphology and neurodegenerative disease pathology.

Clinical Implications

The identification of specific tau filament structures associated with MAPT mutations may provide insights into the mechanisms underlying tauopathies. This knowledge could inform future research and therapeutic strategies targeting tau aggregation.

Conclusion

The structural analysis of tau filaments enhances our understanding of the molecular basis of tauopathies, particularly in relation to specific MAPT mutations. Further research is needed to explore the implications of these findings in clinical settings.