Structural and Kinetic Characterization of Disease-Associated Tau Mutants

  • Author / Creator
    Yarahmady, Allan
  • While great advancements have been made in the field of tau biology, one particularly elusive component is the significance of structural variance of tau aggregates linked to disease: we see great structural heterogeneity among the aggregates obtained from various tauopathies despite being made from the same protein. Furthermore, these profiles appear to be consistent across patients with a given disease. This suggests disease-specific cellular triggers that favour certain aggregate structures over others. A better understanding of these differences would bring us closer to defining the critical early stages of disease onset and spread. One way to study this research question is via saturation mutagenesis. Point mutations in tau can have marked effects on aggregate kinetics, structure, and morphology, so this method would allow for a thorough assessment of the sequence-structure relationship for tau aggregation. To achieve this, a high-throughput method of purifying recombinant tau was optimised to be compatible with downstream assays such as those measuring in vitro aggregation kinetics or aggregate core structures resistant to protease digestion. In this thesis, a preliminary screen of our developed platform was performed on 36 tau mutants linked to the tauopathy FTLD-tau. These mutants were found to group into ten structural subtypes.

  • Subjects / Keywords
  • Graduation date
    Fall 2022
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.