J.G.M. van Scheppingen
- Astrocytes as mediators of inflammation in epilepsy: focus on tuberous sclerosis complex
- Award date
- 14 September 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Tuberous sclerosis complex (TSC) is a genetic disease with an incidence between 1 in 6,000 and 1 in 11,000 births presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Epilepsy is the most prevalent and severe manifestation of TSC, occurring in 70 to 80% of all patients, often already starting early in life. In this thesis, we aimed to investigate the molecular mechanisms of pathology in TSC, in order to find potential targets and novel therapeutic strategies. Additionally, we aimed to evaluate possible functional modulations of inflammatory pathways using in vitro astrocyte cultures. Based on the proportion of calcifications, dysmorphic neurons and giant cells we proposed a new histopathological classification system for cortical tubers in TSC, designated tuber type A, B, and C. We found that inflammatory pathways are amongst the main deregulated systems in TSC tubers and therefore represent excellent targets for further exploration. We identified specific deregulated biological signaling pathways and potential targets for treatment. Using astrocyte cell cultures, we determined functional characteristics of several targets that are deregulated in cortical tubers and our data suggest that miRNAs might be of therapeutic value in the treatment of drug-resistant epilepsy in TSC. Furthermore, results from pre-clinical and clinical studies are encouraging and indicate that miRNAs may have therapeutic value in treating drug-resistant epilepsy. Therefore, the administration of miRNAs could be a promising new therapy in the treatment of epilepsy and TSC.
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