322 - Radical consequences of redox active metals on α-synuclein assemblies

Abstract

Histopathological hallmarks of Parkinson’s disease (PD) include the development of granular inclusions known as Lewy bodies that are enriched with aggregates of the protein α-synuclein (αS). Historically, αS has been considered a natively unfolded protein prone to amyloidogenic behavior. A molecular understanding of how the structurally dynamic nature of this protein contributes to PD symptoms is still lacking, but metal dyshomeostasis has long been linked to PD. Thus, a deeper understanding of biometal-influenced dynamics and metal-mediated redox chemistry associated with each of the various conformational states of αS may shed light on PD pathways associated with cerebral metal miscompartmentalization. Work in our lab is dedicated to the overarching goal of elucidating the mechanistic roles of cerebral biometals, specifically iron and copper, as either protagonistic cofactors or antagonistic toxins. My lab has recently demonstrated the biophysical consequences of metal binding that influence αS structure and aggregation, including an FeII/O2-dependent self-association of αS to a PD-relevant oligomer-locked A11+ species with a high degree of right-twisted anti-parallel b-sheet structure. In this work, we further elaborate the downstream effects of metal-αS interactions, including how aerobically aggregated FeII-bound αS, in particular, promotes protein-protein interactions. Secondary structural deconvolution and identification of proteins with homologous structures have implicated protein partners for αS with significance to PD and other neurodegenerative diseases, and we have verified these interactions through immunological analyses and chemical cross-linking. We have also established the metal-induced generation of protein-based radicals that are distinct to the metal ion identity and that contribute to the structural heterogeneity of αS assemblies. Presentation of this work will offer a unique perspective on both the beneficial and consequential role of prevalent transition metals in the brain.