Functional role of SKAP2 for oligodendroglial migration and myelination

• Applicant: Professorin Dr. Tanja Kuhlmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432961971

Multiple sclerosis (MS) is the most frequent demyelinating disease in the central nervous system and a leading cause for clinical disability in young adults. The histopathological hallmarks of MS are inflammatory demyelinating lesions. Inflammation and permanent demyelination contribute to axonal damage and loss, the cause for the progressive neurological deficit observed in MS patients. Only aggressive ablation of the immune system is able to stop disease progression; however these treatment regimens are associated with severe side effects. Promotion of remyelination combined with immunomodulatory drugs represents an attractive treatment strategy to prevent disease progression and even improve clinical symptoms. Remyelination does occur in MS lesions but is frequently limited, especially in chronic MS lesions. Prerequisite for successful remyelination is migration and differentiation of oligodendroglial progenitor cell; however both processes are disturbed in MS lesions. Whereas the molecular mechanisms of oligodendroglial differentiation are at least partly understood, relatively little is known about oligodendroglial migration. Therefore, the aim of our study is to contribute to the understanding of the molecular mechanisms regulating oligodendroglial migration and to potentially identify new therapeutic approaches to promote remyelination. In preliminary experiments we could demonstrate that SKAP2, an intracytoplamic adaptor protein of src kinases, is expressed in oligodendroglial linage cells in different CNS regions and upregulated during oligodendroglial differentiation. Downregulation and/or lack of Skap2 results in decreased directed and undirected migration as well as reduced myelin sheath formation, but has no effect on oligodendroglial proliferation and differentiation in mature MBP-positive oligodendrocytes. In contrast, overexpression of constitutive active Skap2 increased oligodendroglial migration. Based on these results we want to 1. dissect the up- and downstream signalling cascades of SKAP2, 2. analyze the effect of SKAP2 in human induced pluripotent stem cell derived oligodendrocytes and 3. to determine whether SKAP2 is a drugable target. To address these questions we will perform in vitro and in vivo experiments using mouse and human oligodendrocytes.

• DFG Programme: Research Grants