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Myelin protein impact on membrane phase state, morphology and structure

Myelin is multibilayered, dominantly lipid sheath that enwraps axons and ensures proper transmission of neural impulses. One of the most highlighted compositional attributes of myelin is the domination of lipids (70-85 %) over proteins of which the most significant are proteolipid protein (PLP) and myelin basic protein (MBP) (15-30 %), with representative lipids being phospholipids (phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylserines (PSs) and sphingomyelin (SM)) and cholesterol (chol). Disruption of spirally wrapped myelin sheath around axon axis is refferred as demyelination and it encompasses the effects such as the redundant unwrappping, vacuole formation and bilayer swelling due to water and ions leaking across the sheaths. Resulting with the impaired transmission of neural impulses, it produces clinical symptoms such as vision loss and muscle weakness which are common features of multiple sclerosis (MS). The studies of experimental autoimmune encephalomyelitis (EAE), as animal model of MS, demonstrated that the amount and ratios of representative myelin lipids were significantly modified in contrast with myelin of normal varieties and are further accompanied by reduced adhesive activity of myelin basic protein (MBP). Although extensively explored in vitro and in vivo models, a more detailed picture of the molecular level events that drive the demyelination in all of its forms remains unknown. This project aims to tackle these unknows by examination of model myelin membranes of different sizes and composition (with respect to the normal and modified myelin) in the presence of MBP and its simpler subunits (peptides) that make a direct
interaction with lipid membrane. Model myelin membranes will be prepared as large and giant uni- and multilamellar liposomes (LUVs/GUVs and MLVs/GMVs) and their response to the presence of peptides and MBP will be analyzed with microscopic and spectroscopic techniques, as well with the support provided by molecular dynamics simulations. Aside of understanding  demyelination at the molecular level, obtained results will help in suggesting possible solutions in lipid composition regulation either by medications and appropriate nutrition or will provide the guidelines towards building-up the artificial myelin structure.

Principal investigator: Danijela Bakarić

Spectroscopic insight into the interaction of myelin basic protein and neutral membrane lipids

Small changes in lipid distribution within the myelin membrane may affect its adhesive properties, as well as the binding of myelin basic protein (MBP). MBP is an unstructured positively charged protein which is crucial for lateral organization of multiple myelin bilayers wrapped around the axon of a neural cell. However, the mechanism of interaction between MBP and zwitterionic lipids is still not completely elucidated. The behavior of MBP on the surface of zwitterionic lipid bilayers will be investigated with spectroscopic techniques such as FTIR and UV/Vis spectroscopy, and also with the assistance of computational simulations. Phase transition temperatures of multiple lipid bilayers and their structuration will be detected with or without the addition of MBP, and in different solvation conditions. The information gained from this project will contribute to the investigative efforts towards understanding the role of lipid domains in pathological phenomena such as membrane degradation in neurodegenerative diseases.

Principal investigator: Petra Maleš

Development of spectroscopic techniques in characterization of asymmetric lipid membranes

Drug delivery by liposome encapsulation is mainly dependent on lipid charge, composition and organization. Though the administration of positively charged pharmaceuticals is the most effective within a negatively charged liposome, such liposomes may interact negatively with blood and tissue biomolecules. However, asymmetric liposomes that consist of neutral lipids in the outer layer and negative lipids in the inner layer represent an effective compromise for effective delivery with few adverse effects. Within this project, FTIR spectroscopy will be employed to characterize asymmetric liposomes on the molecular level. Temperature-dependent behavior of lipid functional groups will be used to identify thermal properties of symmetric versus asymmetric liposomes containing the same lipid molecules, and will enable differentiation of their organization. FTIR data will be compared to DSC and NMR results. The information gained from this project will be further utilized for asymmetric liposome development as delivery vehicles.

Principal investigator: Danijela Bakarić

Model of demyelination on a molecular scale at physiological and pathological conditions

Myelin is multibilayered, dominantly lipid sheath that enwraps axons and ensures proper transmission of neural impulses. Loss of myelin integrity in terms of redundant unwrapping, vacuole formation and swelling of the bilayer sheaths is referred as demyelination and is related to multiple sclerosis. In vivo studies reported that the amounts of representative lipids, including phosphatidylethanolamines (PEs), are significantly changed in diseased compared to healthy animals, and are further accompanied by reduced adhesive activity of myelin basic protein (MBP). The impact of the amount of PE in mixed model lipid membranes on the transition temperature between lamellar (La) to inverse hexagonal (HII) phase, where the latter shares structural features with vacuole formation, is significant but rather elusive issue. The aim of this proposal is to establish a link between this temperature change and the size and arrangement of PE domains in mixed model lipid membranes in the presence and absence of MBP. Model myelin membranes will be prepared from representative myelin lipids according to their ratios found in normal and diseased species. La to HII phase transitions of PE domains will be studied by probing different surroundings of PE domains within the bilayer, along with the variations in the hydrating medium regarding the presence of MBP and ionic content. A detailed molecular picture of these events will be provided by combining temperature-dependent IR spectroscopy and computational chemistry; structural changes of PE domain during this phase transition will be identified together with the interactions between PE, MBP and neighboring domains. As a result, the parameters considered as the most critical in reduction of La to HII phase transition temperature will be revealed. Aside of understanding demyelination at the molecular level, obtained results will help in suggesting possible solutions in lipid composition regulation by medications and appropriate nutrition.

Principal investigator: Danijela Bakarić

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