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UBC Theses and Dissertations

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UBC Theses and Dissertations

IPSC-derived GRN-mutant astrocytes delay excitatory electrical development of neurons in a non-cell autonomous manner Lee, Christopher

Abstract

Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are characterized by pathology predominantly localized to the frontal and temporal lobes. FTD is the second leading cause of early-onset dementia behind Alzheimer’s Disease, and there are currently no disease-modifying treatments available. Approximately 40% of FTD cases are familial, and 25% of these are caused by heterozygous loss of function mutations in the gene encoding for progranulin (PGRN), GRN. Since its discovery almost 15 years ago, a plethora of research has attempted to explain the mechanisms for how loss of PGRN leads to FTD, but an entire picture remains unclear. Evidence from murine models has in the past suggested that astrocytes, the main supporting cells of the brain, do not secrete PGRN; however, more recent analysis has shown astrocyte PGRN expression in both murine and human cells. It has also been shown that mutations in MAPT – another leading cause of familial FTD – greatly alters astrocyte gene expression which leads to subsequent non-cell autonomous effects on neurons. In this study, we utilized human induced pluripotent stem cell (hiPSC)-derived neural tissue carrying a homozygous GRN R493X-/- knock-in mutation to investigate in vitro whether GRN mutant astrocytes have a non-cell autonomous effect on neurons. Using microelectrode array analysis, we demonstrated that GRN R493X-/- astrocytes impact neuron maturation by significantly delaying excitatory electrical development. Histologically, neurons during the delay showed a decrease in GABAergic synaptic markers while also showing an increase in glutaminergic synaptic markers. We also demonstrate that this effect is due in-part due to soluble factors, and that GRN mutation alters neurotrophic factor secretion in astrocytes. Overall, this work represents the first study investigating astrocyte-induced neuronal pathology in GRN mutant hiPSCs, and supports the hypothesis of astrocyte involvement in the progression of FTD.

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Attribution-NonCommercial-NoDerivatives 4.0 International