Neurotoxic protein oligomers
Oligomers and fibrils (amyloids) formed from several proteins are associated with a variety of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and ALS. Unfortunately, for many of the proteins involved in these diseases, the mechanisms responsible for amyloid formation and the structures of various intermediates (e.g. oligomers and protofibrils) along the fibrillization pathway are notoriously difficult to study. This is especially true of oligomeric species, which are difficult to isolate, metastable, and disproportionately toxic relative to higher molecular weight protofibrils and fibrils. The continued study of oligomeric species will require breakthroughs in structural biology as well as an improved understanding of protein homeostasis and fibrilization kinetics. We are developing tools that will aid in the isolation of neurotoxic protein oligomers with the ultimate goal of establishing structure-function relationships for these species.