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Huntington’s disease astrocyte and brain-microvascular endothelial cell dysregulation

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Huntington’s disease (HD) is a devastating inherited neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The HD disease-causing mutation affects numerous cellular processes, contributing to overall dysregulated cellular homeostasis in the central nervous system, particularly in the striatum and cortex of the brain. While HD is predominately characterized by the loss of neurons, other non-neuronal cell types have been demonstrated to be significantly affected by mutant HTT; however, characterization of non-cell autonomous effects caused by HTT CAG repeat expansion in non-neuronal cell types was largely lacking prior to initiating this dissertation. Here, I describe my investigation into the cell-autonomous affects caused by mutant HTT through patient induced pluripotent stem cell (iPSC) modeling of two critical cellular regulators of brain homeostasis—brain microvascular endothelial cells (BMECs) and astrocytes. Assessing the dysregulation of HD BMECs and astrocytes provides a clearer understanding of disease pathogenesis and can provide additional knowledge to aid in the development of effective therapeutic interventions needed for HD patients.

This dissertation describes several transcriptomic analyses to provide mechanistic insights into pathways that underlie dysregulated HD iPSCs-derived BMECs (iBMECs) and iPSC-derived astrocytes (iAstros). First, bulk RNA-sequencing (RNA-seq) demonstrated aberrant WNT activation in HD iBMECs that when inhibited pharmacologically, prevented angiogenic deficits and improved paracellular barrier function in iBMECs. Secondly, single-nuclei RNA-seq highlighted inhibited synaptogenesis and glutamate receptor signaling states in both HD iAstros and HD mouse model astrocytes as well as a novel activated actin cytoskeletal signaling cell state unique in HD human astrocytes. HD iBMEC and HD astrocyte studies demonstrated dysfunctional properties that may be due to aberrant developmental trajectories. These data further support the hypothesis that mutant HTT induces dysregulated non-neuronal cell types that promote dysfunctional properties unique to each cell type, contributing to HD pathogenesis. Together, my analyses provide novel insights into molecular mechanisms that contribute to disease pathogenesis, and this knowledge can be used to inform future therapeutic investigations for HD.

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