| dc.description.abstracteng | Axonal integrity and longevity require functionally intact myelin, as demonstrated by the deletion of myelin-specific genes in mice. To identify molecules that contribute to the structural organization of CNS myelin, its protein content was systematically analyzed by quantitative proteome analysis. It was found that filament-forming septins are surprisingly abundant in myelin and we hypothesized that septin filaments may constitute a cytoskeletal membrane cortex. Here, I have investigated the exact subcellular localization and the pathobiological relevance of the septin cytoskeleton in myelinating glial cells. By immunohistochemistry, myelin septins were found to specify a novel subdomain in the internodal adaxonal compartment of CNS myelin, in which they assemble as filamentous structures gently undulating along the internodal segment of axons. Targeted deletion of the Sept8-gene, which encodes the most abundant myelin septin, led to secondary diminishment of SEPT2, SEPT4, SEPT7 and SEPT9 in myelin. SEPT8 is thus essential for the assembly of the CNS myelin septin filament. By quantitative mass spectrometry, the septin-polymerizing protein anillin was also diminished in SEPT8-deficient myelin, demonstrating a reverse effect of septins on anillin. Importantly, the targeted loss of SEPT8 and its associated proteins led to pathological outfoldings of myelin, indicating for the first time that the myelin septin filament prevents the emergence of this very specific pathology. Interestingly, myelin outfoldings alone did not induce axonal pathology or neuroinflammation. Only when further challenged, e.g. by a reduced abundance of the myelin protein CNP or the induction of EAE, the altered myelin structure triggered enhanced neuroinflammation. I have also approached the septin cytoskeleton of peripheral myelin. Interestingly, in Schwann cells, the subunit composition of septin filaments partly differs from that of CNS myelin and septins localize to the abaxonal compartment of peripheral myelin termed the bands of Cajal. The targeted deletion of SEPT8 did not lead to a loss of the PNS myelin septin filament, most likely because of a compensatory increase in the abundance of the closely related SEPT11. Together, septin filaments emerge as a newly identified stabilizer of the myelin sheath with pathobiological relevance. | de |