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

Abstract

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem 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 the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau). In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments 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, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease 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 the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease

“…These differences were revealed by the choice of recombinant tau substrate, polyanionic cofactors, and other reaction conditions, but presumably reflects the underlying conformation(s) of the tau aggregates that accumulate preferentially in the context of AD. Indeed, the recent cryo-EM-based structures of AD and PiD tau filaments have indicated marked differences in their amyloid cores [12–14]. As has been documented with distinct TSE prion strains, we provide evidence that the distinct structures of tau aggregates that accumulate in different diseases have self-propagating activities that were readily distinguished by their relative abilities to seed the polymerization of various tau substrates under suitable conditions.…”

Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

“…In an attempt to gain insight into the structural basis underlying the inhibitory effects of phosphorylation and the relative contribution of each phosphorylation site,w er eviewed the recent high-resolution atomic cryo-EM structures of the tau filaments derived from the brains of patients with AD and Picksd isease. [11,12] Close examination of the structures suggests that phosphorylation of S258 and S262 are likely to influence the Taua ssembly (see Figure S18 A).…”

Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

“…The tau species isolated from proteolytically stable PHF-core preparations from AD brain tissue comprise a mixture of fragments derived from both 3-and 4-repeat isoforms, but restricted to the equivalent of three repeats, with an N-terminus at residues Ile-297 or His-299 (4-repeat numbering) and the C-terminus at residue Glu-391, or at homologous positions in other species [5,6]. The same segment of the molecule, encompassing residues 306-378, has been confirmed as constituting the core of the PHF using cryoelectron microscopy analysis of PHFs extracted from AD brain tissue [7] and a homologous core fragment from 3-repeat tau been identified in the filaments found in some forms of Frontotemporal Dementia (FTD) [8].…”