Elucidation of the etiopathology of protein-metal interactions has been in the spotlight of neurodegenerative disease research for many years. The hallmark protein ?-synuclein (?S), which is associated with the most prevalent movement disorder - Parkinson?s disease (PD), remains unclear in regards to both function and conformation. Similarly, questions pertaining to the role of transition biometals, namely copper and iron, are still a mystery.
This research aims to elucidate the effect of these biometals on different conformational states of ?S, contributing clarity to current controversies surrounding the native structure. In recent years, equally convincing biochemical studies on erythrocyte- and brain-derived ?S protein have been reported that argue in support of two different native conformations for ?S. The conventional conformation of ?S has been described as an intrinsically disordered monomer that can self-associate to form toxic oligomers as well as disease-relevant insoluble aggregates termed Lewy bodies. Recent findings have supported a native tetrameric ?-helical ?S conformation that is stabilized by hydrophobic interactions and that is resistant to aggregation, yet systematic studies are sparse. Comprehensive studies on the role of copper and iron in these native conformations in regards to structural influences, membrane affinity, protein-protein interactions, and/or ability to produce functional/dysfunctional post-translational modifications have yet to be reported. The cross-disciplinary approach described through this research strategy will aid in closing this gap within the biomedical community. Likewise, an advancement in the understanding of tau/?S interactions as well as oxidative and/or nitrosative molecular mechanisms will contribute to the elucidation of pathologically relevant disease pathways associated with PD and may inspire new targets for drug development and/or clinical biomarkers.

Public Health Relevance

Parkinson?s Disease (PD) is the second most prevalent neurodegenerative disorder, and it is one for which there is currently no cure. The biologically relevant conformation of the aggregation-prone protein implicated in PD pathogenesis, ?-synuclein, remains unconfirmed. The proposed research will contribute to a fundamental bioinorganic understanding of the influence of biometals on native conformational protein dynamics and assembly as well as the role of molecular pathways associated with oxidative and/or nitrosative stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM134015-02
Application #
10022129
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Flicker, Paula F
Project Start
2019-09-23
Project End
2024-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298