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Structures of filaments from Pick's disease reveal a novel tau protein fold

By Benjamin Falcon, Wenjuan Zhang, Alexey G. Murzin, Garib Murshudov, Holly J. Garringer, Ruben Vidal, R. Anthony Crowther, Bernardino Ghetti, Sjors Scheres, Michel Goedert

Posted 16 Apr 2018
bioRxiv DOI: 10.1101/302216 (published DOI: 10.1038/s41586-018-0454-y)

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies appear to spread through specific neural networks in each disease, with short filaments having the greatest seeding activity. The abundance of tau inclusions strongly correlates with disease symptoms. Six tau isoforms are expressed in normal adult human brain - three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms lacking the second repeat (3R tau). In various diseases, tau filaments can be composed of either 3R tau or 4R tau, or of both 3R and 4R tau. They have distinct cellular and neuroanatomical distributions, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations. Such conformers may give rise to different neuropathological phenotypes, reminiscent of prion strains. However, the underlying structures are not known. Using electron cryo-microscopy (cryo-EM), we recently reported the structures of tau filaments from Alzheimer's disease, which contain both 3R and 4R tau. Here we have determined the structures of tau filaments from Pick's disease, a neurodegenerative disorder characterised by frontotemporal dementia. They consist of residues K254-F378 of 3R tau, which are folded differently when compared to tau in Alzheimer's disease filaments, establishing the existence of conformers of assembled tau. The Pick fold explains the selective incorporation of 3R tau in Pick bodies and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

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