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Full text release has been delayed at the author's request until December 14, 2025
ETD Abstract Container
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Membrane Interactions of alpha-synuclein
Author Info
Tyoe, Owen
ORCID® Identifier
http://orcid.org/0009-0001-1267-7209
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1733837548821241
Abstract Details
Year and Degree
2024, PhD, University of Cincinnati, Arts and Sciences: Physics.
Abstract
alpha-Synuclein (alpha-syn) is an amyloidogenic protein whose pathological aggregation is associated with Parkinson’s disease and other neurodegenerative diseases known as synucleinopathies. While its physiological function is still in question, it is associated with DNA repair and the regulation of neurotransmitter release via interaction with synaptic vesicles (SVs), including vesicle docking, clustering, and SNARE complex assembly. Even though the association of alpha-syn in Lewy bodies is heavily studied in the field of PD pathology, the details underlying its misfolding in mutant or wild-type form and interactions with other proteins and membranes are of great interest, as the mechanisms of cell death all involve the membrane interaction of alpha-synuclein, in monomeric, oligomeric, or fibril form. The interaction of fatty acids with alpha-syn modulates the formation of aggregates, but it is less clear how fatty acids including DHA modulate the function of alpha-syn in terms of alpha-syn-membrane interactions, but recent studies suggest the preferential solvation of DHA enhances membrane binding of alpha-syn. Cholesterol is a major component of SV membrane, and further the variability of cholesterol in cell membranes affects many macroscopic membrane properties including membrane thickness, packing defects, and membrane permeability/fluidity. Furthermore, cholesterol regulates alpha-syn binding to synaptic vesicles and modifies its aggregation. Using single-molecule optical techniques and all-atom MD simulation, we show that DHA and cholesterol modulation of vesicle clustering mediated by alpha-syn is due primarily to the electrostatic interaction between the membrane and the N-terminal region of alpha-syn. Moreover, the cholesterol modulation of alpha-syn-membrane interaction is nonlinear with respect to the concentration of cholesterol. This work highlights the complexity of interaction between alpha-syn and lipid membranes, and further emphasizes the role of fatty acid and cholesterol levels in membranes and their impact on alpha-syn function. The content of this thesis is split into two parts. First, the methodology of protein-mediated vesicle clustering via TIRF, the determination of protein secondary structure via CD spectroscopy, and the atomic and mechanistic detail underpinning these interactions probed by MD simulation are each discussed. The latter sections of the thesis discuss particular results, with regard to the role of DHA and cholesterol in alpha-syn-membrane interactions and vesicle clustering.
Committee
Colin Bischoff, Ph.D. (Committee Chair)
L. C. R. Wijewardhana, Ph.D. (Committee Member)
Hans-Peter Wagner, Ph.D. (Committee Member)
Jiajie Diao, Ph.D. (Committee Member)
Pages
101 p.
Subject Headings
Physics
Keywords
Proteins
;
Membranes
;
Vesicles
;
Fatty Acids
;
Cholesterol
;
Lipids
Recommended Citations
Refworks
EndNote
RIS
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Citations
Tyoe, O. (2024).
Membrane Interactions of alpha-synuclein
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1733837548821241
APA Style (7th edition)
Tyoe, Owen.
Membrane Interactions of alpha-synuclein.
2024. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1733837548821241.
MLA Style (8th edition)
Tyoe, Owen. "Membrane Interactions of alpha-synuclein." Doctoral dissertation, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1733837548821241
Chicago Manual of Style (17th edition)
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Document number:
ucin1733837548821241
Copyright Info
© 2024, some rights reserved.
Membrane Interactions of alpha-synuclein by Owen Tyoe is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.