Investigating the role of ATF4 in models of Parkinson's disease
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.