PT - JOURNAL ARTICLE AU - Benjamin Falcon AU - Wenjuan Zhang AU - Alexey G. Murzin AU - Garib Murshudov AU - Holly J. Garringer AU - Ruben Vidal AU - R. Anthony Crowther AU - Bernardino Ghetti AU - Sjors H.W. Scheres AU - Michel Goedert TI - Structures of filaments from Pick’s disease reveal a novel tau protein fold AID - 10.1101/302216 DP - 2018 Jan 01 TA - bioRxiv PG - 302216 4099 - http://biorxiv.org/content/early/2018/04/16/302216.short 4100 - http://biorxiv.org/content/early/2018/04/16/302216.full AB - The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies appear to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. 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)1. 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 distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. 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 tau11. 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.