Project description
Insight into the life cycle of myelin
Neuronal axons are insulated by myelin sheaths which ensure that electrical signals are processed at higher speed and with greater efficiency. Myelin is synthesised during development, while later in the adult state it has a limited turnover, and undergoes a degradative phase during ageing. The aim of the EU-funded NETWORK project is to understand how the myelin-producing oligodendrocytes interact with other glial cells at different stages of the myelin life cycle. Understanding how the metabolism of glial cells changes upon myelin degeneration has important consequences for age related conditions and neurodegenerative disorders, such as Alzheimer’s disease.
Objective
Myelin is an abundant, lipid-rich membrane structure formed by oligodendrocytes, each of which extends numerous processes to form distinct myelin internode segments along axons, thereby increasing neural processing speed and energetic efficiency. Myelin undergoes a life cycle with three fundamental distinct phases of metabolism, starting with an ‘anabolic’ phase of early postnatal myelin development, followed by a homeostatic, adult state, in which turnover is low, and ending with a ‘catabolic’, myelin degradative phase in aging. Here, I hypothesize that oligodendrocytes and their myelin sheaths are metabolically connected to other glial cells, and we therefore plan to analyze how the entire glial system interacts during these distinct phases. Key is that lipoproteins may function as vehicles in this communication to connect and regulate lipid metabolism in the cells. We will use systems biology approaches to characterize how astrocytes and microglia respond to myelin assembly and disassembly. I suggest that glial cells serve as a homeostatic control system to balance and buffer changes that occur during the myelin life cycle. This system is relevant in aging, and we therefore plan to analyze how glial cells react and adapt their metabolism to age-related white matter myelin degeneration, and how lipoproteins participate in this process. We will determine the molecular anatomy of the major lipoproteins in the CNS to explore the role of lipoproteins in neurodegenerative diseases to understand both their protective functions as detoxifiers, and also their maladaptive, inflammatory functions driving pathology. We would like to propose a work program, in which we link the fundamental biology of lipid metabolism to myelin in the normal and diseased central nervous system. This approach will not only shed light on myelin biology and lipoproteins function and dysfunction, but may also open the door to new therapeutic venues for neurological disorders.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
80333 Muenchen
Germany