The correlation between conformational states of α-synuclein (αS) and their relationship to Parkinson’s Disease (PD) pathology have evolved in recent years to adopt both a monomeric and tetrameric form.  Traditionally, the conformation of αS was described as an intrinsically disordered monomer that aggregates to form β-sheet fibrils, potentially through oligomeric intermediates.  Tetrameric αS has been characterized as both α-helical and aggregation resistant, likely functioning as a passive storage form of the protein.  The pathological conformation of αS remains controversial but each functional fold and dysfunctional misfold must originate from the monomeric protein.  Membrane-protein interactions are thought to facilitate the transition of monomeric αS to the α-helical tetramer due to the similarity in folding patterns.  Physiological levels of cerebral biometals, such as copper and iron, change in various regions of the brain with aging and with advanced disease states.  Metal dyshomeostasis has long been linked to PD but most of the work predated the discovery of the tetramer and the acceptance of αS as being post-translationally acetylated at the N-terminus.  The presented research will highlight metal-induced changes in the folding pattern of αS and the distinguishable differences observed between various metal oxidation states.  Unique changes are observed in the protein secondary structure and the hydrodynamic radius upon the introduction of stoichiometric quantities of individual metal ions based on biochemical and biophysical analyses. Immunoblotting techniques have revealed that metal-bound αS can follow distinct pathways towards toxic oligomers or β-sheet fibrils depending on the metal.  Furthermore, a clear involvement of ambient oxygen in the production of post-translational modifications has been observed.  Such metal-induced conformational changes result in altered membrane interactions, which could have physiological implications.  Taken together, these results contribute to the ongoing conversation within the field about the role of metals and αS in PD progression.

Conformational changes of α-synuclein induced by copper versus iron

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.