UC Davis

Dysregulation of protein homeostasis and the resultant formation of neurotoxic aggregates and fibrils is thought to be a major contributor to the pathogenesis of neurodegenerative diseases. Protein chaperones have been found to prevent the formation of toxic proteins and facilitate their clearance. However, the molecular mechanisms initiating toxic aggregation and how it is regulated by chaperones is not well understood. This work de-scribes the investigations of fibril assembly of a critical RNA-processing protein linked to several neurodegenerative diseases and describes how a chaperone prevents the primary nucleation of aggregates. Chapter 1 introduces the complexity of cellular proteostasis, de-scribes the functions of a cellular process, stress granules, and links a small heat-shock chaperone to a neurodegenerative disease-relevant protein. Chapter 2 highlights and briefly describes the methods used in the proceeding sections. Chapter 3 details the preparation and optimization of aggregation-prone low complexity domains for biophysical characterization. Chapter 4 provides a deeper mechanistic understanding of chaperone activity as it relates to amyloid formation. Finally, chapter 5 highlights efforts to further characterize effectors of low complexity domain aggregation, demonstrates the efficacy of chaperones on a disease-causing mutant protein, and explores the diagnostic imaging landscape.