Nature: Structure-based classification of tauopathies

  • Abnormal accumulation of misfolded tau in filaments is characteristic of many neurodegenerative diseases—precisely for this reason, these neurodegenerative diseases are collectively referred to as tauopathy. The Michel Goedert team and the Sjors Scheres team at the Molecular Biology Laboratory of the Medical Research Council in Cambridge, UK, witnessed the use of cryo-EM to dissect tau filament (tau) structures in tauopathies such as Alzheimer's disease, primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), Pick's disease, and corticobasal degeneration (CBD) in a long-term collaboration with each other.


    Today, in a new study, the Goedert team and the Scheres team collaborated again with long-term collaborators Bernardino Ghetti from Indiana University School of Medicine in the United States and Masato Hasegawa from the Tokyo Institute of Medical Sciences in Japan to solve tau filament structures in eight other tauopathies. Their findings suggest a hierarchical classification of tauopathy, which has important implications for future diagnostic and therapeutic approaches. The relevant findings were published online in Nature, and the paper was entitled "Structure-based classification of tauopathies".


    As with previous tau protein diseases, these authors used neuropathologically confirmed brain tissues from human disease cases to extract tau protein filaments and analyzed their structure using cryo-electron microscopy. On the basis of previously studied diseases, they now dissect the structure of tau filaments in progressive supranuclear palsy (PSP), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), aging-related tau astrocytoma (ARTAG), familial British dementia (FBD), familial Danish dementia (FDD), and hereditary cases carrying mutations in introns + 3 and + 16 of the microtubule-associated protein tau gene (MAPT).


    Until then, tauopathy was mainly characterized by clinical diagnosis and postmortem neuropathology. Combined with their previous work, these findings of cryo-electron microscopy suggest a new, layered approach and use this to classify tau filament folding in tauopathy. This approach also prompted these authors to identify a new disease, named limbic-predominant neuronal inclusion body 4R tauopathy (LNT), and based on the observation that the tau filament structure of a patient diagnosed with PSP was different from that of all other patients.


    In addition, this approach provides a new way to study similarities and differences between diseases. For example, it has been suggested that PSP and CBD are closely related because they are both clinically similar 4-repeat tauopathies. However, this new study found that tau filament folding in PSP and CBD is more different than one might think. In fact, after solving the structure of tau filaments in PSP, they discovered a new three-layer fold. Cryo-EM analysis showed that tau filaments in PSP are more similar to those in GGT, while tau filaments in AGD are different from PSP because of their four-layered folding, but similar to tau filaments in CBD. Tau protein filaments showing the folding of tau protein filaments in AGD were also found in the mutation cases of intron 10. Finally, the structure of tau protein filaments in FBD and FDD cases is the same as in Alzheimer's disease and PART.

    This new classification method complements previous clinical diagnostic and neuropathological approaches and allows the identification of new tauopathies. Although different tau filament folds are constituted by the same protein, they cause different diseases. The molecular mechanisms underlying the folding formation of these different tau filaments remain unknown and are an ongoing research topic for the Michel and Sjors teams. Deciphering these mechanisms will have a huge impact on the diagnosis and treatment of tauopathy.