Human N-acetylated α-synuclein (NacαSyn) has long been accepted as an intrinsically disordered protein (IDP) predominantly found in terminal nerve regions in healthy subjects. Its structural fluidity enables formation of transient or dynamic assemblies, some of which may serve functional but as-of-yet undefined purposes. Yet, NacαSyn can also misfold under certain environmental conditions, leading to its aggregation in the form of toxic oligomers or amyloid fibrils. These misfolded NacαSyn inclusions, along with their accretion and migration, are known as pathological hallmarks of Parkinson’s disease (PD), dementia, and multiple system atrophy (MSA). Isolation protocols from human tissue samples have revealed the co-existence of a labile, yet physiologically relevant structured tetrameric conformation (TαSyn) in dynamic equilibrium with its disordered monomeric counterpart. Our studies corroborate previous reports that the TαSyn complex has substantial α-helical secondary structure and the ability to maintain its discrete structural conformation when challenged with environmental conditions that stimulate aggregation of its monomeric counterpart; this latter feature gives TαSyn notable appeal as a potential PD drug target. Advanced computational analyses suggest that TαSyn maintains resilience by burying its hydrophobic self-aggregating NACore region, stalling toxic oligomerization. The mechanism, however, for TαSyn formation and disassembly remains elusive. Considering metal dyshomeostasis (Cu, Fe, Mn) plays a fundamental role in a variety of neurodegenerative disorders, biometal binding may disclose an intimate relationship. Circular dichroism (CD) and folding determination through secondary-structure deconvolution and light-scattering have revealed permutations in TαSyn architecture upon metal coordination. Moreover, immunoassay studies suggest divergent folding/unfolding pathways that are guided by redox cycling and the associated global folding dynamics. Our studies provide insight into metal-mediated TαSyn structural modulation that is dictated by the redox environment. Promiscuous metal coordination and subsequent structural modulation may enable a targetable approach to influence the monomer-tetramer dynamic equilibrium and asymmetry of early PD stages.

Discerning the stability of tetrameric N-acetylated α-synuclein in the presence of redox active biometals

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

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