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. 2020 Nov 4:14:581936.
doi: 10.3389/fnins.2020.581936. eCollection 2020.

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

Fuyuki Kametani  1 , Mari Yoshida  2 , Tomoyasu Matsubara  3 , Shigeo Murayama  2 , Yuko Saito  4 , Ito Kawakami  1 , Mitsumoto Onaya  5 , Hidetomo Tanaka  6 , Akiyoshi Kakita  6 , Andrew C Robinson  7 , David M A Mann  7 , Masato Hasegawa  1
Affiliations

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

Fuyuki Kametani et al. Front Neurosci. .

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.

Keywords: amyloid; cryo-EM; fibril structure; phosphorylation; post-translational modifications; tau; tauopathy; ubiquitination.

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Figures

FIGURE 1
FIGURE 1
Representative images of brain tissue from patients with various tauopathies, stained with AT8 antibody. Characteristic tau inclusions of each tauopathy were detected. Black bar is indicates 50 μm.
FIGURE 2
FIGURE 2
Immunoblot analysis of sarcosyl-insoluble fractions obtained from brain tissues of patients with various tauopathies. After SDS-PAGE using on 4∼20% polyacrylamide gradient gels, immunoblotting were was performed with anti-tau C-terminus antibody T46. Lane 1, AD1; lane 2, AD2; lane 3, FTDP17T1; lane 4, FTDP17T2; lane 5, CBD1; lane 6, CBD2; lane 7, GGT1; lane 8, GGT2; lane 9, PSP1; lane 10, PSP2; lane 11, PiD1; lane 12, PiD2.
See this image and copyright information in PMC

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