The role of astrocytes in neurodevelopmental disorders modelled with Fragile X syndrome
Year: 2025
Type: dissertation
Abstract: Fragile X syndrome (FXS) is a monogenic form of autism and intellectual disability. The underlying cause of FXS is epigenetic silencing of Fragile X messenger ribonucleoprotein 1 (FMR1) gene and subsequent loss of FMR1 protein (FMRP). Due to the key role FMRP plays during early differentiation in the brain, its loss in neuronal progenitors induces changes in the formation of neural circuits and synaptic plasticity. Although originally thought to be exclusively expressed in neuronal cells, astrocytic expression of FMRP has also been confirmed. Astrocytes have been shown to contribute to FXS pathophysiology including aberrant dendritic morphology, synaptic maturation and enhanced neuronal excitation. Most of the existing studies on FXS astrocytes have been conducted on mouse models although murine and human astrocytes display significant species-specific differences. As an alternative, patient-derived induced pluripotent stem cells (iPSCs) provide a tool to produce human FXS astrocyte lines that can be used for disease modelling in vitro. In this thesis work, the aim was to study functional properties of FXS neuronal progenitor cells (NPCs) and the effects of early differentiation defects on the maturation and function of astrocytes. FXS NPCs displayed increased intracellular calcium ([Ca2+]i) signalling mediated by L-type voltage-gated Ca2+ channels affecting the specification of glutamatergic NPCs. Altered signalling was linked to increased levels of brain-derived neurotrophic factor (BDNF) in FXS NPCs. Astrocyte differentiation was modelled using iPSCs. A novel method for the generation of human astrocyte cell lines of forebrain lineage was established and the generated cell lines were confirmed to express both astrocyte and forebrain markers indicating that the initial patterning was successful. Transcriptomic profiling revealed differences between FXS and control astrocytes, including differential expression of genes related to plasminogen system. Both mRNA and secreted protein levels of urokinase plasminogen activator (uPA) were increased in FXS astrocytes affecting both the functional properties of generated astrocytes as well as cortical rat neurons treated with FXS astrocyte-conditioned medium (ACM). Enhanced Tropomyosin-related kinase B (TrkB) phosphorylation induced by FXS-ACM treatment suggests that disrupted uPA signalling contributes to changes in the regulation of synaptic plasticity in FXS. Taken together, these results indicate defects in the functional properties of both FXS NPCs and astrocytes. We further show that human FXS astrocytes display transcriptional and functional changes and identified dysregulation in the levels of uPA indicating a potential underlying mechanism for altered neuronal plasticity. The method developed here serves as a platform for the modelling the role of astrocytes in FXS but can also be used to explore the role of astrocytes in other neurodevelopmental or neurodegenerative disorders as well.
Source: Työväentutkimus Vuosikirja
Author: Peteri, Ulla-Kaisa
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7197131903