Nothing is perfect, and this includes the ability to maintain homeostasis within the cell with age. Factors such as aging, chemicals, and gene dysfunction disrupt cellular homeostasis, leading to increased stress and compromising the ability of animals to maintain a healthy lifespan. Dysregulated homeostasis can be detrimental on an organismal level, impacting locomotion, and on a cellular level causing proteins to misfold and become aggregates, which are toxic to cells. Toxic protein aggregation and loss of locomotory function are key hallmarks of several age-related diseases. My Ph.D. work examined the collapse of homeostasis on electrotaxis, the age-associated increase in proteotoxicity, the decline in longevity, and neuronal and muscle health. On a behavioural level I demonstrated that loss of various components of the MT-UPR, ER-UPR, and HSR modulated the speed of animals. Additionally, I found that activation of stress responses due to chemicals and exercise reduced and increased the speed of animals respectively. On a cellular level I elucidated potential mechanisms by which Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF) affects the stress response to maintain homeostasis and prevent protein aggregation. I observed the novel localization and role of MANF in lysosomes to potentially act as a critical regulator of the stress response to maintain proteostasis, neuronal health and longevity, thereby bringing balance to the cell. Furthermore, the broad tissue expression of MANF revealed its localization to muscles. This supports the ability of MANF to act as more than a neurotrophic factor as it was found to be required for muscular health in animals in an age-dependent manner. Overall, my Ph.D. research has provided new insights into the stress response and behaviour and the precise role of MANF in mediating stress response signaling to promote organismal and cellular fitness. / Dissertation / Doctor of Science (PhD) / Cellular perturbations or stress disrupt homeostasis, activating multiple stress responses. Activation of the stress response can determine the fate of an organism and is crucial to its health. Although the stress response pathways are generally understood, little is known about how the stress responses preserve animal behaviour or how they are regulated to promote organismal survival. My work has provided a basis for how stress responses affect behaviour positively and negatively in animals. I found that the stress response required mesencephalic astrocyte derived neurotrophic factor (MANF) to promote organismal survival. My thesis determined that MANF acts as more than a neurotrophic factor. MANF was found to not only be essential in neuronal health but also longevity and muscle health. Overall, this thesis demonstrated the impact of stress response on behaviour and the potential mechanism by which MANF is cytoprotective in whole organisms.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29686 |
| Date | January 2024 |
| Creators | Taylor, Shane |
| Contributors | Gupta, Bhagwati, Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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