Targeting the Prion-like Aggregation of α-synuclein in Parkinson's Disease and Mutant p53 in Cancer

Protein misfolding results in devastating neurodegenerative diseases and cancer. Key proteins involved in these diseases, such as Aβ, tau, α-synuclein, SOD1, and TDP43 can show a prion-like behavior. In the case of the intrinsically disordered protein (IDP) α-synuclein, we used high hydrostatic pressure to identify the mechanism through which α-syn amyloid fibrils are dissociated into monomers. We provide molecular evidence of how hydrophobic interaction and the formation of water-excluded cavities jointly contribute to the assembly and stabilization of the fibrils. We investigated the structural and dynamic properties of these monomers dissociated from HHP-disturbed fibrils and the remaining fibrillar species at the atomic level, and examined how these species might seed amyloid fibril formation. We are now examining the disassembly profile of disease-related mutants of α-syn to evaluate the potential use of intermediates as targets for drug development. In the case of p53, the function of this tumor suppressor protein is lost in more than 50% of human cancers. Studies from our laboratory and others have demonstrated that the formation of prion-like aggregates of mutant p53 is associated with loss-of-function, dominant-negative and gain-of-function (GoF) effects. p53 aggregates in a mixture of oligomers and fibrils that sequestrates the native protein into an inactive conformation. These aggregates are present in tissue biopsies of breast cancer especially in more aggressive ones. We will present data on (i) the loss-of-function (LoF), dominant negative activity (DN) and gain-of-function (GoF) effects of prion-like mutant p53 aggregation in cancer; (ii) discuss current challenges in preventing p53 aggregation, including the use of small molecules with high anticancer potential; and (iii) describe our methodology for trapping aggregation precursor states in solution.