ORCID

https://orcid.org/0009-0002-2189-0535

Date of Award

2025

Document Type

Thesis

Degree Name

MS in Chemistry

Department

Chemistry

First Advisor

Frank X Vazquez

Second Advisor

Richard Rosso

Third Advisor

Erica Jacobs

Abstract

Parkinson’s Disease (PD) is a neurodegenerative movement disorder which has been found to target the dopaminergic neurons of the substantia nigra. It is characterized by the formation of masses known as Lewy Bodies, formed by aggregates of the intrinsically disordered protein (IDP) -synuclein (asyn). Research suggests that alpha synuclein can undergo aggregation in the presence of heavy metals, which may accumulate in the body through a variety of mechanisms. To study how metals may play a role in wildtype (WT) asyn aggregation, MD simulation of the protein was performed in the presence of bioactive transition metals including Fe2+, Fe3+, Cu+, Cu2+, Zn2+, and Mn2+ ions to observe the proteins behavior. This was done by monitoring changes in polymeric properties, exposure, secondary structure, and interdomain communication. In the study it was found that the protein observed drastic changes and general trends in these properties, many of which were consistent in the different metal-bound systems compared to the metal-free protein. In addition to finding different binding-sites and changes in the protein’s behavior, certain motifs including the positioning of specific amino acid residues as a result of metal-binding were observed, which are suggested to prime the protein-metal complex for further pathways involved in PD biomolecular pathology such as oxidative, nitrosative, and nitrative stress were observed. Finally, future work was suggested to explore the precise molecular mechanisms by which these metals influence asyn aggregation, as well as other biologically relevant mutations and post-translationally modified variants of asyn. These insights lay the groundwork for a deeper understanding of PD pathology and the potential environmental factors involved.

Download

Share

COinS