January 21, 2026
UChicago chemists gain insight into how a Parkinson’s-associated protein binds to membranes in the brain
The exact cause of Parkinson’s disease is still a mystery, but one specific protein found abundantly around neuron synapses seems to play a key role.
Parkinson’s is part of a family of neurodegenerative disorders characterized by an accumulation in the brain of harmful clumps made of a protein called α-synuclein.
These clumps—or aggregates—are created by α-synuclein misfolding thought to occur when it fails to bind correctly to lipid membranes inside neurons, a dysfunction with both genetic and environmental factors.
A study conducted by UChicago chemists recently published in PNAS looked at how the composition and arrangement of lipids in a membrane affect how α-synuclein binds to it. They discovered that membranes require gaps between the lipids (lipid-packing defects) for successful binding.
First author Miah Turke, PhD’25, a graduate student in Ka Yee C. Lee’s Chemistry Department group at the time of this research, describes the experiment’s goals, major findings, and next steps.
(See Turke's "pocket thesis" below, a visual overview of this research and more.)
What was the goal of this research?
The goal was to understand more about how Parkinson’s disease–associated protein α-synuclein interacts with lipid membranes. The exact healthy function of the protein is unknown, but both its function and dysfunction relate to its interaction with lipid membranes in the brain. We wanted to understand this interaction in more detail.
More specifically, we wanted to understand how changing the lipids in the membrane affects the way the protein binds, which could give insight into how the protein binds to different membranes. The results could also potentially illuminate how aging-associated changes in brain lipids could affect the way the protein binds—which could in turn give insight into protein dysfunction.
How was the study carried out?
We took advantage of the fluorescent properties of the amino acid tryptophan, which has a different fluorescence emission spectrum in hydrophobic versus hydrophilic environments (“unbound” in solution versus “bound” buried in the membrane).
We placed tryptophans at each end of the binding region of the protein, allowing us to decipher how much of each end was bound to a given membrane. Comparing the binding of these tryptophan reporters gives an idea of how the protein’s configuration, or its folded shape or orientation, may vary on membranes with different properties.
We measured the binding through tryptophan fluorescence to model membranes with different properties conferred through differences in lipid composition, such as net negative charge and lipid packing density.
What are the key findings?
It was previously thought that α-synuclein required negatively charged lipids to bind to a membrane. However, we found that lipid packing defects—or increased spacing between lipids in a membrane—are more important for α-synuclein-membrane binding than overall negative charge.
We saw that the protein bound significantly to membranes with no net charge when they had ample packing defects but did not bind at all to membranes with minimal defects and high net negative charge.
We additionally found that decreasing lipid packing defects on a membrane can alter the protein’s configuration on the membrane, when altering charge does not. This suggests that lipid packing defects determine 1) if α-synuclein binds to a membrane at all, 2) how it binds to the membrane, and 3) how much it binds to a membrane. Altering net negative charge only determines how much α-synuclein binds.
What are the big-picture implications of these findings?
Overall, a better understanding of the parameters which affect the interaction between α-synuclein and lipid membranes not only could provide critical puzzle pieces for understanding the protein’s functions as it relates to different membranes, but it could also help us understand how the protein-membrane interaction may become diseased.
Previous work from our group demonstrated a conserved shift in how seven Parkinson’s disease–associated mutations of α-synuclein bind to the membrane—a shift toward a membrane-bound configuration that is partially unbound. This same configuration was found to be favored by wild type (WT) protein on low-defect membranes in the present study. This shared bound configuration in Parkinson’s disease mutants and WT α-synuclein on low-defect membranes provides a link between diseased states to changes in lipid packing defects.
Only a small percentage of Parkinson’s cases are genetic, and lipid compositional changes in the brain are increasingly linked with the disease. Thus, it is possible that lipid compositional changes in the brain that decrease packing defects (through decreases in polyunsaturated fatty acids or increases in saturated lipids) could be altering the bound configuration of the protein, potentially priming it for aggregation.
What are the next steps?
Next steps for this work include aggregation studies of the protein in the presence of membranes with different amounts of charge and lipid packing defects. It will be important to see if the altered bound configuration of the protein on low-defect membranes is correlated with an increase in aggregation.
Overall, this study highlights the importance of the membrane—an often-underappreciated player in biology—in protein function and potentially disease.
Citation: M.J. Turke, K.M. Raghavan, S. Maltseva, D.H.S. Kerr, E.J. Adams, & K.Y.C. Lee, Lipid-packing defects are sufficient to modulate membrane insertion and the bound state of α-synuclein, Proc. Natl. Acad. Sci. U.S.A. 122 (52) e2419823122, https://doi.org/10.1073/pnas.2419823122 (2025).
Illustrated science