TY - JOUR
T1 - Tau strains shape disease
AU - Vaquer-Alicea, Jaime
AU - Diamond, Marc I.
AU - Joachimiak, Lukasz A.
N1 - Funding Information:
Work in the Diamond lab is supported by the NIH (1R01AG048678-01A1, 1R01AG059689-01A1, 1R01NS089932-01A1 to M.I.D) and a Chan Zuckerberg Initiative Collaborative Science Award (2018-191983 to J.V.A and M.I.D.). L.A.J. was supported by the Marie Effie Cain Endowed Scholarship, a Chan Zuckerberg Initiative Collaborative Science Award (2018-191983) and a Bright Focus Foundation Grant (A2019060). We thank members of the Diamond and Joachimiak labs for discussions. We also thank Dr. Rati Chkheidze for providing histological neuropathology images.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Aggregation
KW - Amyloid
KW - Diagnosis
KW - Folding
KW - Polymorph
KW - Prion
KW - Propagation
KW - Self-assembly
KW - Strains
KW - Tau
KW - Tauopathy
KW - Therapeutics
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U2 - 10.1007/s00401-021-02301-7
DO - 10.1007/s00401-021-02301-7
M3 - Review article
C2 - 33830330
AN - SCOPUS:85104049119
VL - 142
SP - 57
EP - 71
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 1
ER -