Molecular mechanisms of myelin clearance in demyelinating lesions

• Applicant: Professor Dr. Mikael Jakob Simons
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320251040

Myelin is generated by the spiral wrapping of oligodendrocyte plasma membrane around axons of the central nervous system. The result is the formation of tightly packed multilamellar membrane composed of closely associated and long-lived molecules. We have studied the mechanisms of myelin turnover and the contribution of the innate immune system in this process. We now plan to extend our studies to diseases using mouse models of demyelinating disorders. In myelin disorders large amounts of lipid-rich, tightly packed and, thus, hard-to-digest myelin membrane are constantly broken down and released into the extracellular space. Such a release may not only overwhelm the degradation capacities of the phagocytising microglia and macrophages, but could also result in the accumulation of toxic lipid species.Here, we want to test whether lipid overloading in microglia/macrophages represents the Achilles heel in tissue repair. We aim to study whether lipid overload in microglia/macrophages results in an inflammatory response, inhibition of remyelination and neurotoxicity in demyelinated lesions of the CNS. We hypothesize that these events triggers a maladaptive inflammatory response in microglia which involves the inflammasome pathway.We hope that our planed research will lead to the design of novel experimental strategies of how to promote lipid efflux from demyelinating lesions in order to promote remyelination and protect neurons from degeneration.

• DFG Programme: Research Grants