Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Cregan, Sean P
Abstract
Parkinson’s disease is the second most common neurodegenerative disease. This disease primarily affects the motor system, and symptoms of bradykinesia, resting tremors, and rigidity are often present in patients. At the molecular level, these deficits are caused by a loss of striatal dopamine due to the death of dopaminergic neurons in the substantia nigras. Currently, the mechanism underlying neuronal death in PD remains unknown. Both oxidative and proteostatic stress are thought to be contributing factors to neuronal death in PD. The Integrated Stress Response (ISR) and Activating transcription factor-4 (ATF4) is a cell signaling pathway that can respond to diverse stress stimuli such as oxidative and proteostatic stress. When transiently activated, the ISR functions to restore homeostasis however, prolonged activation may promote cell death. The role of ATF4 in promoting cell survival or cell death is currently controversial in PD. Considering this, the goal of this thesis is to determine the effect ATF4 has in models of Parkinson’s disease. Using primary mouse neurons, we have established that 1) ATF4 is a pro-death factor which results in loss of dopaminergic neurons and 2) uncovered the novel mechanism by which sustained ATF4 induction promotes activation of pro-apoptotic protein PUMA through suppression of mTOR signaling pathway. In addition, we report the generation and molecular characterization of a dopamine-specific ATF4 knockout mouse that will be foundational for dissecting the role of ATF4 in preclinical in vivo models of disease. Taken together, the findings from this thesis highlight the role of ATF4 in dopaminergic neuron loss in models of Parkinson’s disease and provide potential molecular targets that may be exploited in future therapeutic development.
Summary for Lay Audience
Parkinson’s disease (PD) is a brain disease that commonly affects aged individuals. People with PD often face debilitating motor symptoms that progress with time. Patients will often be characterized based on their resting tremors and inability to properly control voluntary movements. At the cellular level, this disease is caused by the loss of a specific type of neuron that produces a brain molecule called dopamine. Loss of these neurons from a specific region in the midbrain results in decreased levels of dopamine which causes the movement disorder. Several factors are thought to contribute to cell dysfunction in PD. For example, oxidative stress or protein aggregation may attack and damage neurons. In mammals, there is a stress response pathway called the Integrated Stress Response (ISR). This pathway can be activated in response to different stress conditions. When this pathway is turned on, it results in the increased activity of a gene called Activating Transcription Factor-4 (ATF4). ATF4 can then affect the expression of other genes which may promote cell survival or when turned on for too long, promote cell death. In this thesis, we have demonstrated that sustained ATF4 levels are sufficient to kill dopaminergic neurons in models of Parkinson’s disease. Furthermore, we have discovered that this occurs by a mechanism in which a key cell survival signaling hub called mTOR is suppressed. In addition to these findings, we have generated a mouse model in which ATF4 has been specifically removed from dopaminergic neurons. This will allow us to study the role of ATF4 in complex animal behavior and brain degeneration in preclinical models of PD. Ultimately, these results point to ATF4 has being responsible for the loss of dopaminergic neurons and provide insights for the development of future therapeutics.
Recommended Citation
Demmings, Matthew D., "Investigating the role of ATF4 in models of Parkinson's disease" (2024). Electronic Thesis and Dissertation Repository. 10131.
https://ir.lib.uwo.ca/etd/10131
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.