Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target.

Sebastian S Oakley,Mahmoud B Maina,Louise C Serpell,Karen E Marshall,Claude M Wischik,Charlie R Harrington,Youssra K Al-Hilaly

doi:10.3389/fneur.2020.590754

Abstract

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors.

Highlights

Synthesized and unfolded proteins must undergo a carefully controlled folding process to produce their specific biologically active conformation, known as the native state
This study suggests a possible link between amyloid β (Aβ), induction of tau post-translational modification (PTM) and the initiation of tau self-assembly into filaments [160]
The studies revealed that these filaments lack essential features of Alzheimer’s Disease (AD) paired helical filament (PHF), such as the interface between PHF6 and its opposing residues 373–378. These findings indicate that heparin-induced filaments of T40 tau are both structurally heterogeneous and distinct from those found in the disease brain, challenging their reliability for use in a tau self-assembly model or as an assay for screening potential inhibitors

Summary

Introduction

Synthesized and unfolded proteins must undergo a carefully controlled folding process to produce their specific biologically active conformation, known as the native state. No differences in the primary amino acid sequence have been identified in the tau fragment extracted from PHF preparations, which indicates that any pathological processing of tau associated with PHF assembly must be induced by conformational or post-translational changes in the protein [75, 117, 118].

Results

Conclusion