Title: Misfolding and aggregation of disease-related proteins studied at the single molecule level
Abstract: The misfolding and aggregation of proteins is involved in a wide variety of diseases, especially neurodegenerative disorders like prion diseases, Alzheimer's, Parkinson's, and ALS. However, the mechanisms by which proteins convert into non-native structures and aggregate remain poorly understood at the molecular level. I will discuss recent work studying the formation of non-native structures in single molecules and small oligomers of two disease-related proteins: PrP, which causes prion diseases, and α-synuclein, which is related to Parkinson's. Using optical tweezers to apply forces to individual protein molecules, we can observe the unfolding and refolding of these proteins, and distinguish the formation of native vs non-native structures. With PrP, we find that isolated molecules do not form stable misfolded structures, although they can fold into a variety of unstable non-native structures. In contrast, two PrP molecules linked in tandem always form a single stable misfolded structure. For α-synuclein, which is intrinsically disordered, we find that the protein can fold into a wide variety of metastable structures, and as more α-synuclein molecules are linked in tandem to form oligomers, the complexity of these structures increases. We use these measurements to determine the energy landscape that drives the conformational dynamics of the proteins, and we also explore the effects of potential drugs that inhibit misfolding and aggregation, elucidating their mechanism of action at the molecular level.