Site of Cholesterol Oxidation Impacts Its Localization and Domain Formation in the Neuronal Plasma Membrane

Abstract

Cholesterol is integral to the structure of mammalian cell membranes. Oxidation of cholesterol alters how it behaves in the membrane and influences the membrane biophysical properties. Elevated levels of oxidized cholesterol are associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Previous work has investigated the impact of oxidized cholesterol in the context of simple model membrane systems. However, there is a growing body of literature that shows that complex membranes possessing physiological phospholipid distributions have different properties from those of binary or trinary model membranes. In the current work, the impact of oxidized cholesterol on the biophysical properties of a complex neuronal plasma membrane is investigated using coarse-grained Martini molecular dynamics simulations. Comparison of the native neuronal membrane to neuronal membranes containing 10% tail-oxidized or 10% head-oxidized cholesterol shows that the site of oxidization changes the behavior of the oxidized cholesterol in the membrane. Furthermore, species-specific domain formation is observed between each oxidized cholesterol and minor lipid classes. Although both tail-oxidized and head-oxidized cholesterols modulate the biophysical properties of the membrane, smaller changes are observed in the complex neuronal membrane than seen in the previous work on simple binary or trinary model membranes. This work highlights the presence of compensatory effects of lipid diversity in the complex neuronal membrane. Overall, this study improves our molecular-level understanding of the effects of oxidized cholesterol on the properties of neuronal tissue and emphasizes the importance of studying membranes with realistic lipid compositions.

Effects of Nitro-Oxidative Stress on Biomolecules: Part 1—Non-Reactive Molecular Dynamics Simulations

“…Structural analysis of both types of oxidation revealed that oxysterols with oxidized tails have a similar effect on membrane fluidity as normal cholesterol. They increase the order of phospholipids, reduce lateral diffusion, and decrease membrane fluidity [ 115 , 122 ]. Tail-oxidized cholesterol mostly orients parallel to the bilayer normal in each leaflet, with its hydroxyl group positioned toward the head groups of phospholipids near the water interface.…”

“…Tail-oxidized cholesterol mostly orients parallel to the bilayer normal in each leaflet, with its hydroxyl group positioned toward the head groups of phospholipids near the water interface. In contrast, oxysterol with an oxidized ring behaves somewhat differently than normal cholesterol [ 122 ]. It induces a greater tilt angle in membrane phospholipids and significantly disrupts membrane structure compared to tail-oxidized and normal cholesterols [ 115 , 122 ].…”

“…In contrast, oxysterol with an oxidized ring behaves somewhat differently than normal cholesterol [ 122 ]. It induces a greater tilt angle in membrane phospholipids and significantly disrupts membrane structure compared to tail-oxidized and normal cholesterols [ 115 , 122 ]. (CAP-generated) RONS primarily produce ring-oxidized cholesterol [ 115 ], which can reduce membrane fluidity.…”

Oxidation of Membrane Lipids Alters the Activity of the Human Serotonin 1A Receptor

“…36−39 Cholesterol oxidation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. 40 Changing the concentration of phosphatidylethanolamine lipids and cholesterol alters rhodopsin equilibrium, demonstrating the effects of membrane lipid composition on this key model GPCR. 41−44 We have previously demonstrated that both 5-HT 1A R and A 2A R will localize to phase-separated domains in a membrane in a composition-dependent manner.…”

“…GPCR function is known to be coupled to the composition of the plasma membrane. For instance, it is well documented that changes in membrane cholesterol homeostasis lead to several GPCR-related disease pathologies. , Additionally, cholesterol oxidation affects its localization and membrane biophysical properties, leading to membrane thinning, increased permeability, and reduced lipid order. − Cholesterol oxidation is associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease . Changing the concentration of phosphatidylethanolamine lipids and cholesterol alters rhodopsin equilibrium, demonstrating the effects of membrane lipid composition on this key model GPCR. − We have previously demonstrated that both 5-HT 1A R and A 2A R will localize to phase-separated domains in a membrane in a composition-dependent manner. , We have also shown that the functional activity of 5-HT 1A R depends on membrane order .…”