APR 27, 2022 9:00 AM PDT

Tale of amyloid filaments in neurodegenerative diseases


Date:  April 27, 2022
Time: 9:00am (PDT),  12:00pm (EDT), 6:00pm (CEST)
Abnormal accumulation of misfolded tau protein in filaments characterizes more than 20 neurodegenerative diseases—collectively called tauopathies. Most of these diseases can be attributed to mutations in tau gene. Cryo-electron microscopy (cryo-EM) has been used to solve the structures of tau filaments extracted from diseased brain tissue of neuropathologically confirmed cases of Alzheimer's disease, primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), Pick's disease, and corticobasal degeneration (CBD). This study led to over 40 high resolution structures of tau filaments found in all these different tauopathies. On top of the previously studied diseases, we have also determined the structures of tau filaments from a further eight tauopathies including progressive supranuclear palsy (PSP) and argyrophilic grain disease (AGD). These cryo-EM findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new tauopathies.
Different diseases are distinguished by different tau folds. To understand the relevance of these folds we require better model systems which can recapitulate this in vitro. This study led to the high-resolution structure determination 76 structures of recombinant tau filaments assembled in vitro, providing a new database for the greater amyloid field. Understanding their molecular mechanism holds important implications for future diagnostic and treatment approaches.
Learning Objectives
  • Review amyloid filaments and neurodegenerative diseases
  • Define what are taupathies and how are they related to neurodegenerative diseases
  • Describe how high throughput cryo-EM can help identify new tauopathies
  • Relate future opportunities and how these structures can be used for Pharma intervention
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