Friday, May 9, 2025
5/9/2025
The ISR pathway in Dopamine Neurons: Perpetrator or Protector in Parkinson's Disease - Project Abstract Parkinson's disease is the leading cause of movement disorders and currently there are no disease‐ modifying therapies available. Parkinson's disease is associated with progressive and selective degeneration of dopamine neurons in the substantia nigra pars compacta, however the exact biological mechanisms underlying dopamine neuron susceptibility remains unknown. Current working models for many neurodegenerative diseases, including Parkinson's disease, is that runaway activation of cell stress response pathways in response to disease‐relevant pathology exacerbate and drive neuronal death. However, stress response pathways are also required for cell survival and restoring homeostasis. One such pathway is the integrated stress response (ISR), which is a biochemical pathway that responds to various forms of internal and external cellular stress to regulate protein translation. Activation of the ISR results in a global reduction of protein synthesis, and also a selective increase in cell survival genes that are regulated by the transcription factor ATF4. While triggering the ISR is a key mechanism to protect a cell from a stressor, prolonged and excessive activation of the ISR can lead to cell death through apoptosis. In advanced disease stages of Parkinson's, both human pathological studies and mouse models show evidence of high ISR activation. This has led to the idea that dysregulation of the ISR could be one driver of PD pathophysiology, and that inhibiting the ISR would be beneficial. However, no studies have investigated the role of the ISR in pre‐disease states or the role of the ISR specifically in brain dopaminergic neurons. It was recently discovered by our lab that the ISR is not just used as a stress response pathway in a class of neuromodulatory cells (cholinergic interneurons), but rather, these cells basally constitutively engage this pathway to maintain proper biological and electrophysiological function. This work unveiled a novel role for the ISR in some neurons in a normal, non‐disease or exogenous cell stress state. When looking at other high firing neuromodulatory cells, we found that dopaminergic neurons showed a broad range of ISR activity states, from low/off to high. I hypothesize that subclasses of dopamine neurons share the cholinergic neuron phenotype of having an activated ISR state normally. I further hypothesize that, in contrast to the idea that a high ISR accelerates disease pathogenesis, a higher ISR state basally, pre‐insult protects neurons better from future cell stressors. This hypothesis is based on the concept of hormesis. In this proposal, I will examine ISR states in dopamine neuron subclasses in health and PD mouse models and bidirectionally test how dopamine neuron ISR state modifies cell death and disease progression.
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