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Single-molecule force spectroscopy of alpha-synuclein Open Access


Other title
protein misfolding
optical tweezers
single molecule force spectroscopy
Type of item
Degree grantor
University of Alberta
Author or creator
Solanki, Allison K
Supervisor and department
Woodside, Michael T (Physics)
Examining committee member and department
Plotkin, Steven (Physics and Astronomy, UBC)
Sim, Valerie (Medicine)
Freeman, Mark (Physics)
Tuszynski, Jack (Physics)
Department of Physics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Intrinsically disordered proteins (IDPs) represent a large subpopulation of the proteome, and are characterized by high structural plasticity and a predisposition to aggregate. These aggregates can accumulate inside or outside the cell, often forming amyloid plaques that are implicated in a variety of maladies, including Alzheimer’s disease, type II diabetes and Parkinson’s disease. Despite many advances in elucidating aggregation mechanisms, much is still unknown about the early oligomeric states, which are the suspected toxic agents in disease, since their transient nature makes them hard to study with traditional experimental methods. Here we have investigated the initial stages of aggregation of one such IDP, α-synuclein, a protein that is involved in Parkinson’s disease and other related dementias. To do so, we developed assays for characterizing the transient structure, stability, and kinetics of monomers and oligomers using optical tweezers with high spatial and temporal resolution. Measurements of the molecular extension as the proteins unfolded under tension revealed that even small oligomers could form numerous metastable structures, with a surprisingly broad range of sizes. Moreover, our data also revealed rapid fluctuations at low force, arising from the folding of two different classes of structure that were only marginally stable. The energy landscape for these transitions was characterized via the force-dependent kinetics derived from correlation analysis of the extension trajectories. The barriers were small, only a few kBT, but the diffusion was slow, revealing a landscape that is flat but rough. This thesis presents the first measurements of α-synuclein using optical tweezers, and also provides the first experimentally reconstructed energy landscape for an IDP.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Solanki, A., Neupane, K., Woodside, M.T. (2014) Single-molecule force spectroscopy of rapidly-fluctuating, marginally-stable structures in the intrinsically-disordered protein α-synuclein. Physical Review Letters 112(15): 158103.Neupane, K., Solanki, A., Sosova, I., Belov, M., Woodside, M.T. (2014) Diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy. PLoS One 9(1): e86495.

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