Metal Induced Conformational Changes of Alpha‐Synuclein and the Role of Ambient Oxygen

Abstract

Hypotheses surrounding the native conformational states of α‐synuclein (αS), which is known to be a key player in 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. Upon interaction with membranes, this monomeric conformation of αS is known to shift from its dynamic unfolded state to α‐helical. Tetrameric αS has been characterized as both α‐helical and aggregation resistant, likely 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 latter has shown biophysical variation in regards to both αS conformational dynamics and metal coordination. 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 circular dichroism and dynamic light scattering analyses respectively. Under oxidatively stressed conditions, metal‐bound αS can promote the generation of reactive oxygen species. 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.Support or Funding InformationSupported by Virginia Commonwealth University, College of Humanities & Sciences