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

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.

Insight into membraneless organelles and their associated proteins: Drivers, Clients and Regulators

“…Table 6 shows the proteins and the PTMs associated with a disease pathology. For example MAPT PTMs are linked with Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and argyrophilic grain disease (AGD), diabetes among others [56] , [50] .…”

Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

“…2C). The possibility of K317 being posttranslationally modified is unlikely, as mass spectrometry has shown that this site is not ubiquitinated in multiple PSP cases (18). The cofactor attached to K317 bears a remarkable similarity in size and shape to a non-tau density connected to K290, K294, and K370 in tau filaments from multiple CBD cases (7,8).…”

“…3C). Since PSP tau filaments have fewer posttranslational modifications than other tauopathies and are more prone to enzymatic digestion (18), these surface-exposed amino acid sidechains are primed for the development of diagnostic and therapeutic small molecules.…”

“…What has emerged is that the tau protein aggregates in an isoform-specific manner, adopting unique shapes that define the templated growth of filaments in 3R, 3R/4R, and 4R tauopathies (28). Mediating the structural diversity of these tau filaments are disease-specific patterns of posttranslational modifications (7,18) and, in at least three tauopathies (CTE (23), CBD (7,8), and PSP), buried cofactor molecules. This study has identified a novel form of structural diversitymolecular polymorphism -whereby the same 4R tau isoforms adopt two dramatically different folds.…”

“…2, A and B). Unlike the posttranslational modifications which decorate the exposed surface of tau filaments in multiple diseases (7,18), buried non-tau densities may represent small, negatively-charged molecules, e.g., phospholipids, bound to positively-charged lysines. This has been demonstrated for tau filaments from CBD (7,8), and now for PSP (Fig.…”