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Elucidating the role of astrocyte dysfunction in the aetiology of Parkinson’s disease

Li, Zongze ORCID: 2023. Elucidating the role of astrocyte dysfunction in the aetiology of Parkinson’s disease. PhD Thesis, Cardiff University.
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Astrocytes support neuronal survival and function and have been shown to play a role in the aetiology of Parkinson’s disease (PD). Several studies have attempted to generate induced pluripotent stem cell (iPSC)-derived astrocytes from the LMX1A+-derived ventral midbrain (VM) lineage to study the role of astrocytes PD. However, the lineage identity of these astrocytes was poorly characterised. This thesis characterises the lineage identity of iPSC-derived LMX1A+-derived VM astrocytes in comparison to the LMX1A--derived midbrain and telencephalon astrocytes. Using an LMX1A-BFP lineage tracing system, the highly enriched LMX1A+-derived VM lineage progenitors were purified using fluorescence-activated cell sorting. Flow cytometry lineage tracing during the progenitor expansion and astrocytic induction of these progenitors found a loss of the LMX1A+-derived VM lineage progenitors in the unsorted culture but not the sorted culture. Both the remaining progenitors in the unsorted culture and the sorted LMX1A+-derived VM progenitors could be differentiated into astrocytes expressing classic astrocyte makers. Using deep SMART-seq single-cell RNA sequencing, the single-cell transcriptome of astrocytes differentiated from the LMX1A+-derived VM, LMX1A--derived midbrain and the telencephalon lineage. In silico prioritisation and in vitro validation identified FOXG1 and EMX2 as markers for telencephalon astrocytes, NR2F2 and LMO3 for LMX1A+-derived VM astrocytes, and PAX3, PAX7, and IRX3 for LMX1A--derived midbrain astrocytes. Finally, functional assays demonstrated that the LMX1A+-derived VM astrocytes could remove extracellular glutamate, respond to pro-inflammatory stimuli by secreting interleukin 6, exhibit ATP-induced calcium spikes, and protect neurons from oxidative stress in co-culture. LMX1A+-derived VM astrocytes also differentially expressed higher levels of several PD risk genes, most interestingly, SNCA, GBA, and PARK7, suggesting a potential link to PD. This thesis demonstrates that culture heterogeneity affects the lineage identity of iPSCderived VM astrocytes and highlights the need for better and more careful characterisation of the regional identity of stem cell-derived astrocytes.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 29 September 2023
Last Modified: 29 Sep 2023 14:15

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