Tau strains shape disease

Abstract

Tauopathies consist of over 25 different neurodegenerative diseases that include argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Tauopathies are defined by brain accumulation of microtubule-associated protein tau in fibrillar aggregates, whose prevalence strongly correlates with dementia. Dominant mutations in tau cause neurodegenerative diseases, and most increase its aggregation propensity. Pathogenesis of tauopathies may involve pathological tau conformers that serve as templates to recruit native protein into growing assemblies and also move between brain cells to cause disease progression, similar to prions. Prions adopt pathological conformations, termed “strains,” that stably propagate in living systems, and create unique patterns of neuropathology. Data from multiple laboratories now suggest that tau acts as a prion. It propagates unique strains indefinitely in cultured cells, and when these are inoculated into mouse models, they create defined neuropathological patterns, which establish a direct link between conformation and disease. In humans, distinct fibril structures are associated with different diseases, but causality has not been established as in mice. Cryo-EM structures of tau fibrils isolated from tauopathy brains reveal distinct fibril cores across disease. Interestingly, the conformation of the tau monomer unit within different fibril subtypes from the same patient appears relatively preserved. This is consistent with data that the tau monomer samples an ensemble of conformations that act as distinct pathologic templates in the formation of restricted numbers of strains. The propensity of a tau monomer to adopt distinct conformations appears to be linked to defined local motifs that expose different patterns of amyloidogenic amino acid sequences. The prion hypothesis, which predicts that protein structure dictates resultant disease, has proved particularly useful to understand the diversity of human tauopathies. The challenge now is to develop methods to rapidly classify patients according to the structure of the underlying pathological protein assemblies to achieve more accurate diagnosis and effective therapy.

Deep learning reveals disease-specific signatures of white matter pathology in tauopathies

“…These stratifications could then be correlated with or refined by clinical outcomes. Furthermore, it is known from biochemical studies [ 19 , 31 , 36 ], and more recently cryo-EM studies that different protein strains are present in tauopathies and other neurodegenerative diseases (e.g., synucleinopathies). Thus, a key question, as we continue to obtain structural insights from these strain differences, is how structural similarity at the protein level maps to morphological similarity at the aggregate level and how these relations predict disease spread within the brain.…”

Recent update on the heterogeneity of the Alzheimer’s disease spectrum

“…These data also indicate that tau-atrophy variability represents different biologically relevant subtypes, thus documenting the phenotypic heterogeneity of AD (Das et al 2021). The propensity of a tau monomer to adopt distinct conformations appears to be linked to defined local motifs that expose different patterns of amyloidogenic amino acid sequences (Vaquer-Alicea et al 2021). However, the molecular link between Aβ plaques and NFTs is still unclear.…”

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

“…Similar observations regarding prion-like propagation and spreading of pathology and the existence of conformational strains have also been extended to other proteins, most notably Tau and the associated tauopathies. A comprehensive review of these findings was recently compiled by Vaquer-Alicea et al [119].…”