Author ORCID Identifier
https://orcid.org/0009-0009-1050-3940
Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Chemistry
First Advisor
Dr. Heather R. Lucas
Abstract
Parkinson’s Disease (PD) is the world’s second most common neurodegenerative movement disorder. The substantia nigra from PD patients have revealed proteinaceous inclusions termed Lewy Bodies (LBs) primarily composed of a-Synuclein (aSyn). In humans, aSyn is N-terminally acetylated (NAcaSyn), altering the preferred binding sites for CuII and FeIII. The binding effects of each metal ion alone has been reported but not for dual metal coordination to NAcaSyn. Simultaneous coordination resulted in a decrease in parallel and an increase in antiparallel b-sheets. Binding of CuII accelerates the formation of parallel b-sheets, coordination of FeIII inhibits this, while dual metal coordination further modulates the rate of their formation. FeIII binds preferentially to NAcaSyn, though upon aggregation CuII outcompetes FeIII at their shared D121 binding site. Additionally, NAcaSyn is known to form dityrosine crosslinks, a recognized biomarker for PD, and it’s possible for the phenolic radicals created during their formation to covalently couple to form other post-translational motifs, such as isodityrosine, which was investigated herein. Thermo Fisher DynabeadsTM coupled with an antidityrosine antibody were employed as an attempt to isolate dityrosine crosslinks in naturally aggregated NAcaSyn samples and those in which crosslinks were photochemically induced. The DynabeadsTM were unable to completely isolate dityrosine crosslinks due to saturation of the coupled antibody. Although, the results suggest that NAcaSyn may cleave after 8.5 days under natural aggregation conditions and is still capable of forming dityrosine crosslinks. All results reported herein help to uncover more information about the role of NAcaSyn in the pathogenic mechanism of PD.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-16-2024