Brinkman, Judith (2025) Microglia-specific subtype dependent loss of MERTK expression in the normal appearing white matter of primary progressive MS patients. thesis, Medicine.
Full text available on request.Abstract
Background: MS is a central nervous system (CNS) disease, primarily affecting myelin, the insulating matter surrounding CNS axons in young adults. Two progressive forms of MS exist: primary and secondary progressive MS (PPMS and SPMS). The cause and pathophysiology of MS are not fully understood, and no cure exists. MS is characterized by focal white and grey matter lesions due to myelin damage, while the surrounding white matter appears ‘normal’ and is indistinguishable from healthy brain tissue. However, emerging evidence suggests that the NAWM may provide critical information about MS pathogenesis. In this study, we aimed to identify and validate molecular changes in the NAWM of progressive MS patients to discover potential therapeutic targets. Methods: Overlapping differentially expressed genes (DEGs) were identified from 3 MS gene expression datasets. Based on the top 10 DEGs, AXL, MERTK, TYRO3 and TYROBP were selected for downstream validation. 5 controls, 4 PPMS and 6 SPMS donors were included for gene expression analysis in the NAWM using RT-qPCR. MERTK expression in astrocytes and microglia was analyzed at protein level through immunofluorescence on tissue from 3 selected non-MS controls, 3 PPMS and 3 SPMS donors. RT-qPCR was performed in in vitro cultured murine astrocytes and microglia under inflammatory conditions. Results: 242 overlapping genes with altered expression in MS brain tissue were identified. AXL, MERTK, TYRO3 and TYROBP showed enriched expression in the NAWM of progressive MS types. Immunofluorescence revealed more MERTK-positive astrocytes and fewer MERTK+ microglia in PPMS, while the NAWM of SPMS donors showed only an increase in MERTK+ astrocytes. The overall intensity of MERTK immunofluorescence showed no difference in either cell types. In vitro cultured murine astrocytes/microglia showed no MERTK amplification. Conclusion: This study demonstrates significant changes in the expression of TAM receptors in glial cells within the NAWM of progressive MS, which suggests dysfunctional phagocytosis. The difference in MERTK expression in microglia between progressive MS subtypes indicates a microglia-dependent loss of MERTK expression specifically in the NAWM of PPMS patients which makes MERTK a potential therapeutic target in the treatment of PPMS.
| Item Type: | Thesis (UNSPECIFIED) |
|---|---|
| Supervisor name: | Castorina, Alessandro and Baron, Wia |
| Faculty: | Medical Sciences |
| Date Deposited: | 06 Feb 2026 14:18 |
| Last Modified: | 06 Feb 2026 14:18 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/3887 |
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