Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies.

Fuyuki Kametani,Mitsumoto Onaya,Andrew C Robinson,Yuko Saito,Masato Hasegawa,Hidetomo Tanaka,David M A Mann,Shigeo Murayama,Ito Kawakami,Mari Yoshida,Tomoyasu Matsubara,Akiyoshi Kakita

doi:10.3389/fnins.2020.581936

Abstract

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.

Highlights

Neurodegenerative tauopathies are characterized by cytoplasmic aggregates of hyperphosphorylated tau protein (Goedert et al, 1992; Buee et al, 2000; Lee et al, 2001)
We have been investigating the sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer’s disease (AD), Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or and FTDP-17T, and we previously reported that the carboxyl-terminal region of tau, which constitutes the trypsin-resistant core units of tau aggregates, shows different banding patterns among the diseases (Taniguchi-Watanabe et al, 2016)
Alzheimer’s disease, FTDP-17T, CBD, glial tauopathyPost-translational Modifications of Pathological Tau (GGT), PSP, and PiD were neuropathologically diagnosed and biochemically confirmed by immunoblotting with anti-tau antibodies

Summary

Introduction

Neurodegenerative tauopathies are characterized by cytoplasmic aggregates of hyperphosphorylated tau protein (Goedert et al, 1992; Buee et al, 2000; Lee et al, 2001). In PSP, CBD, GGT, and AGD, 4R tau isoforms selectively accumulate in neuronal and glial cells, and the filaments in each disease have unique filamentous morphologies, such as SFs (13–14 nm) in PSP and wide, twisted filaments (20 nm) in CBD (Iwatsubo et al, 1994; Spillantini et al, 1997; Hutton et al, 1998; Poorkaj et al, 1998; Buee and Delacourte, 1999; Goedert and Hasegawa, 1999; Lee et al, 2001; Kovacs, 2015). It has been reported that CBD and PSP can be distinguished biochemically based on the characteristics of the C-terminal fragments (Arai et al, 2004) and the band patterns of protease-resistant fragments (TaniguchiWatanabe et al, 2016), even though they are both 4R tauopathies

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