Functional role of SKAP2 for oligodendroglial migration and myelination
Final Report Abstract
Current multiple sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail due to insufficient understanding of its underlying mechanisms. Current concepts suggest, that disease progression is driven by a combination of persisting inflammation in the brain and failure of brain plasticity and remyelination. Therefore, promotion of remyelination represents a promising treatment strategy. In rodent demyelinating animal models, proliferation and migration of OPC as well as the differentiation of OPC into mature myelinating oligodendrocytes are pre-requisite for successful remyelination. Mature oligodendrocytes may also contribute to remyelination; however to which extent and whether the same is true in MS is currently a matter of debate. In previous studies, we observed a higher migratory migration capacity of spinal cord OPC (scOPC) compared to compared to brain OPC (cOPC) and we identified SKAP2 as a potential regulator of oligodendroglial migration. SKAP2 is a cytoplasmatic adaptor protein known for its implication in cytoskeletal remodelling and migration in other cell types. Downregulation or complete lack of SKAP2 in OPC resulted in reduced migration and impaired morphological maturation of mouse oligodendrocytes, whereas overexpression of SKAP2 as well as constitutively active SKAP2 increased OPC migration. Similarly, knockdown of SKAP2 in human iPSC derived oligodendrocytes decreased migration as well. By phosphor arrays and immunocytochemistry, we identified CRKII and pVASP as potential up- or downstream members of the SKAP2 signalling cascade. However, knockdown of Fyn, CrkII and Vasp had in contrast to knockdown of Skap2 no effect on oligodendroglial migration. RGD, an integrin ligand, increased OPC migration and OPC lacking Skap2 displayed an increased directed migration suggesting that SKAP2 modulates integrinmediated migration. In a next step, we elucidated whether SKAP2 might be a promising pharmaceutical target to promote oligodendroglial migration. In collaboration with Sergio Baranzini we performed an in silico screen based on machine learning to identify potential compounds promoting oligodendroglial migration via SKAP2. However, none of the compounds we tested, had a positive effect on oligodendroglial migration. Moreover, to facilitate the studying of the functional roles of candidate genes and the identification of promyelinating compounds in a human pre-clinical model, we developed a rapid and reproducible protocol for generation of human myelinating brain organoids. In summary, we identified SKAP2 as a regulator of migration in mouse and human oligodendrocytes. Furthermore, we provide evidence that SKAP2 is involved in integrinmediated directed migration and we developed a human pre-clinical model to test the promyelinating capacities of pharmacological compounds.
Publications
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SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation. Glia, 69(11), 2699-2716.
Ghelman, Julia; Grewing, Laureen; Windener, Farina; Albrecht, Stefanie; Zarbock, Alexander & Kuhlmann, Tanja
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Inflammation in multiple sclerosis: consequences for remyelination and disease progression. Nature Reviews Neurology, 19(5), 305-320.
Klotz, Luisa; Antel, Jack & Kuhlmann, Tanja
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Microglia activation in periplaque white matter in multiple sclerosis depends on age and lesion type, but does not correlate with oligodendroglial loss. Acta Neuropathologica, 146(6), 817-828.
Kessler, Wiebke; Thomas, Christian & Kuhlmann, Tanja
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Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS. Acta Neuropathologica, 147(1).
Windener, Farina; Grewing, Laureen; Thomas, Christian; Dorion, Marie-France; Otteken, Marie; Kular, Lara; Jagodic, Maja; Antel, Jack; Albrecht, Stefanie & Kuhlmann, Tanja
