Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau

Abstract

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer’s disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7–18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243–406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1503-3) contains supplementary material, which is available to authorized users.

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

“…Inoculation of brain lysate from five different tauopathy syndromes generated disease-associated tau prion strain patterns in a cell model (Sanders et al, 2014). These observations were consistent with prior studies based on brain homogenate inoculations into mice (Boluda et al, 2015; Clavaguera et al, 2013), and additional work based on biochemical analysis of aggregates from patient brain (Taniguchi-Watanabe et al, 2015). Furthermore, some patients appear to be afflicted by multiple tau prion strains (Sanders et al, 2014), reminiscent of previous findings regarding PrP prion strains isolated from single patients with CJD (Polymenidou et al, 2005; Puoti et al, 1999).…”

HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

“…Additionally, proteolysis assays indicate that patient-derived fibrils from different tauopathies have distinct morphologies (53). An understanding of the diversity of tau fibril morphologies thus remains an important open question.…”

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies

“…These tracers are in principle ligands that bind to a b-pleated sheet secondary structure forming in tau filaments, and are likely to dock a binding pocket on the b-sheet of tau, which may differ structurally from binding pockets in amyloid-b fibrils (Berriman et al, 2003). Similarly, there may be conformational and structural differences among tracer binding components on distinct tau fibril strains, particularly in with respect to tau isoform compositions (Hasegawa et al, 2014;Taniguchi-Watanabe et al, 2016), since an alternative splicing domain, exon 10, is a constituent of the b-sheet domain of fibrillary tau assemblies (Li et al, 2002;von Bergen et al, 2006;Daebel et al, 2012).…”