Florey Department of Neuroscience and Mental Health - Theses

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Author: Asadian, Negar × End date: 2023 × Start date: 2020 × Type: PhD thesis ×

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    Interrogating TAM receptor activation for therapeutic benefit in multiple sclerosis
    Asadian, Negar ( 2023-05)
    Multiple sclerosis is an autoimmune neurodegenerative disease characterized by demyelination and axonal damage in the central nervous system (CNS). Remyelination plays a crucial role in axonal protection and functional recovery. The GAS6 protein has emerged as a promising candidate for enhancing remyelination. This thesis aims to uncover the underlying mechanisms through which GAS6 exerts its pro-myelinating effect. Additionally, it delves into the pharmacokinetic properties of this protein, emphasizing the significance of gamma-carboxylation in the GAS6 GLA domain in mediating myelination in vitro, along with its residence time in the CNS. The latter part of this doctoral work demonstrates the utilization of the PEGylation approach to extend the brief CNS residence time of the GAS6 protein. The data from this project suggest that the Tyro3 receptor significantly contributes to GAS6's pro-myelinating effect in the CNS after demyelination. This observation appears to be partly driven by mature oligodendrocytes and seems largely independent of the inflammatory response. This research also underscores the importance of gamma-carboxylation within the GAS6 GLA domain for its pro-myelinating effect in vitro. Additionally, it reveals that GAS6 exhibits a short residence time of less than two hours in the murine brain. Using the PEGylation approach, a bioactive variant of this protein with an extended CNS residence time was successfully generated. In summary, this work identifies the Tyro3 receptor as a potential target for the GAS6 pro-myelinating effect and sheds light on some pharmacokinetic properties of the GAS6 protein, particularly highlighting the significance of its post-translational modifications and brief CNS residence time.