Chaperone effects on tau amyloid formation

Abstract

Tau is a microtubule-associated protein that forms insoluble amyloid fibrils in a set of neurodegenerative disorders termed tauopathies, which include Alzheimer’s disease, frontotemporal dementia, and chronic traumatic encephalopathy. Molecular chaperones are proteins that act to prevent aberrant protein aggregation such as tau fibril formation. This dissertation characterizes the mechanisms by which chaperones interact with tau to counteract its aggregation, with particular focus on the small heat shock protein HspB1. Chapter 2 compares the effects of HspB1 on tau aggregation with the effects of another structurally-unrelated chaperone, Hsc70. Chapter 3 describes interactions between the disordered N-terminal region (NTR) and the structured alpha-crystallin domain (ACD) of HspB1. Both domains are involved in chaperone activity toward tau. Understanding how they interact with each other enables further structural characterization of interactions between HspB1 and tau in Chapter 4. Chapter 4 also identifies a way by which interactions between the NTR and ACD can be perturbed to improve HspB1 chaperone activity against tau.