Date of Graduation


Document Type


Degree Type



School of Medicine



Committee Chair

Gordon P Meares

Committee Co-Chair

Timothy D Eubank

Committee Member

David M Smith


Improper protein folding and trafficking are common pathological events observed in various cell types in neurodegenerative diseases. If the protein quality control mechanisms of the endoplasmic reticulum (ER) fail to re-establish proteostasis, misfolded proteins accumulate within the lumen of the ER and perturb normal cellular processes. While low-level stimulation of the unfolded protein response (UPR) is considered a beneficial physiological response to transient protein misfolding stress, or ER stress, sustained UPR activation resulting from prolonged ER stress can promote neurotoxicity. The cell-autonomous mechanisms of the UPR have been extensively characterized in the context of neuropathology. Nevertheless, there still remain unanswered questions regarding the cell-extrinsic role of the UPR under normal physiology, and how this mechanism is compromised in diseased states. To address this, we evaluated whether transferring conditioned media from ER stressed astrocytes to different cell types could modulate their functional characteristics. Our results indicate that ER stressed astrocytes secrete a mediator(s) which regulates both inflammatory and ER stress responses in other astrocytes and neurons in vitro. Initial exposure to this stress factor(s) confers resistance against subsequent ER stress to neurons by engaging the adaptive signals of the neuronal UPR. However, persistent exposure to this unidentified mediator(s) suppresses the initial protective effect and becomes cytotoxic. Overall, these findings provide insight into the cell-nonautonomous influence of ER stress on cells of the central nervous system. Further understanding the molecular mechanisms underlying this mode of intercellular communication would present novel therapeutic opportunities to treat neurodegenerative diseases.