Lipid metabolism in remyelination: does a hidden dialogue exist between the central nervous system and the periphery?

Gouna, Garyfallia (2024): Lipid metabolism in remyelination: does a hidden dialogue exist between the central nervous system and the periphery?. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Inflammatory demyelinating disorders of the central nervous system (CNS) manifest through the pivotal features of myelin disruption and imbalanced inflammation. Within this category, multiple sclerosis (MS) emerges as a major member, distinguished by the formation of demyelinated lesions induced by inflammation. In response to demyelinating stimuli, the CNS initiates a regenerative process known as remyelination, wherein the active participation of glial cells serves to resolve inflammation and promote repair. However, during the progressive phase of MS, remyelination fails, leading to the exacerbation of disease symptoms. The objective of remyelination is to reinstate the integrity of disrupted myelin sheaths, which predominantly consist of lipids. Lipid metabolism in the CNS is of paramount importance as it fulfills crucial functions in structural support, signaling, and energy storage. Lipids hold a central role in remyelination as the phagocytosis of myelin debris, followed by the intracellular process and extracellular efflux of debris lipid components contribute to a successful lesion repair. Simultaneously, the upregulation of de novo lipid biosynthesis, such as cholesterol, also facilitates the regenerative response. Whereas the significance of lipid metabolism in remyelination has only recently begun to be elucidated, the majority of research in this field focuses on local processes within the CNS. New studies indicate that aberrant systemic metabolism, as observed in conditions like obesity, influences the process of remyelination. Nevertheless, the mechanisms through which peripheral lipid metabolism impacts lesion recovery and the inflammatory capacity remain poorly understood. Thus, in this thesis, I aimed to bridge the existing knowledge gap by exploring, in two distinct projects, how lipid metabolism in both the CNS and the periphery influences the regenerative capacity upon acute demyelination. In Project 1, I investigated the role of lipid storage in microglia/macrophages (phagocytes) and its influence on the process of remyelination. I discovered that the conversion of free cholesterol into cholesterol esters and the subsequent formation of lipid droplets (LD) in phagocytes are essential prerequisites for the process of remyelination. When phagocytes fail to generate LD, the resolution of inflammation is impaired and ultimately remyelination proves unsuccessful. I also found that mice lacking the triggering receptor expressed on myeloid cells 2 (TREM2) fail to produce LD due to their incapability to adapt to surplus cholesterol exposure, consequently leading to the development of endoplasmic reticulum (ER) stress. Mitigating ER stress in TREM2-deficient mice restores LD formation and the inflammation is resolved. Thus, I concluded that the biogenesis of LD in response of acute demyelinating injury constitutes a protective mechanism crucial for the remyelination process. In Project 2, I explored the role of dysregulated peripheral lipid metabolism on the remyelination response. Utilizing a murine model that recapitulates the phenotype of lipodystrophy, I discovered that, after acute CNS demyelinating stimuli, lesion repair is promoted, while the inflammation is resolved. Metabolomic analysis revealed increased levels of branched-chain amino acids (BCAAs) and numerous phosphatidylcholine (PCs) species with polyunsaturated long-chain fatty acids (LCFAs) in the plasma of lipodystrophic mice. Successive proteomic analysis indicated a metabolic activation of brown adipose tissue (BAT) via stimulated thermogenesis. The activation of thermogenesis via the uncoupling protein 1 (UCP1)-dependent pathway, however, did not result in enhanced lesion repair. Therefore, I concluded, that, upon demyelinating injury, lipodystrophic mice exhibit enhanced remyelination and resolution of inflammation, mediated in a UCP1-independent way. In a nutshell, both projects of my thesis aimed to examine the role of lipid metabolism in the context of remyelination, in an effort to gain a deeper understanding of the molecular mechanisms that govern the regenerative process, in order to promote efficient treatment strategies. Undoubtedly, lipids stand at the core of this intricate process, urging further appreciation and investigation into their crucial significance.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: lipid metabolim, lipid droplet, cholesterol, trem2, neuroscience, remyelination, CNS, adipose tissue, metabolites, fatty acids, ER stress, BCAAs
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 26. Februar 2024
• 1. Bericht­erstatter:in: Simons, Mikael