Oxidative stress is unquestionably connected to neurodegeneration and is a common feature of the most common movement disorder, Parkinson’s disease (PD). Cerebral hallmarks of PD include the development of insoluble deposits known as Lewy bodies that are enriched with aggregates of the misfolded protein α-synuclein (αS). A molecular understanding of how this structurally dynamic protein contributes to PD symptoms is still lacking, but oxidative cascades that result from metal dyshomeostasis have long been suspected. We previously reported that CuI/O2 induces the formation of protein-based radicals that lead to intermolecular Y39-Y39 dityrosine crosslinks during the fibrillization process, verified through high-resolution mass spectrometry and immunoblotting. During the CuI-to-CuII oxidation process, long-distance interactions between a histidine at position 50 and the N-terminal CuI site are required for dimerization, indicating a key role for metals in modulating the global protein dynamics of αS. Through our studies, we have confirmed that the copper coordination site governs the aggregation rate and that the tyrosine residues involved in coupling reactions influence the aggregation profile. In contrast, we have also established that FeII/O2 promotes the formation of an antiparallel oligomer-locked conformation stabilized by Schiff base formation that prohibits fibrillization. Taken together, the dynamic landscape of αS assembly depending on the coordinated metal identity suggests that the local metal concentration may have pathological relevance. In fact, an altered iron and copper composition within the substantia nigra pars compacta region of the brain is directly associated with PD. Given the important role of transition metals in the brain, we have also considered a functional role for copper and iron, discovering unique metal-promoted protein-protein crosstalk and the stabilization of intricate oligomeric species that may serve as future drug targets to inhibit aggregation. Inspired by Nature, we have also synthetically developed robust bioinorganic coordination complexes that mitigate oxidative processes. Through the implementation of bioinorganic tricks, the ability to both map and offset oxidative cascades carries the potential to address the devastating consequences of PD, which affects millions of people worldwide.

Controlling α-synuclein assembly through metal coordination and/or O2 activation

ACS Spring Meeting 2021

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