Differences in Intrinsic ISR Activation Determine the Susceptibility of Dopamine Neurons to Degeneration in Parkinson’s Disease

Abstract

The integrated stress response (ISR) is a conserved biochemical pathway regulating protein synthesis in response to diverse cellular stressors. Although traditionally studied for its acute role in stress responses, emerging evidence highlights its involvement in modulating neuronal function, plasticity, and behavior under steady-state conditions. Recent findings demonstrate that sustained ISR activation is crucial for maintaining the function of specific neuromodulatory neurons, such as striatal cholinergic interneurons. Using functional ISR reporters, molecular hallmarks, and transcriptional signatures, I identified distinct steady-state ISR activation profiles across regionally and genetically defined subsets of midbrain dopamine neurons in mice and humans. ISR activation generally follows a dorsomedial gradient, with the ventral tegmental area (VTA) and medial substantia nigra pars compacta (SNc) exhibiting the highest basal activity. Notably, this activation pattern aligns with dopamine neuron populations that show greater resistance to degeneration in human neurodegenerative diseases. To assess the functional impact of basal ISR activity on dopamine neuron survival, I bi-directionally manipulated ISR signaling and evaluated vulnerability using an alpha-synuclein overexpression model. My results reveal that ISR activity acts as a potent, cell-autonomous regulator of dopamine neuron susceptibility. Importantly, chronic enhancement of ISR activity through deletion of CReP—a regulatory subunit of the eIF2α phosphatase—was well tolerated across dopamine neuron subclasses and provided protective effects, likely by mitigating acute stress responses. Collectively, these findings suggest that the intrinsic level of ISR engagement in dopamine neurons serves as an endogenous, hormesis-like resilience mechanism against secondary insults and demonstrate the therapeutic potential of chronically enhancing ISR activity to promote dopamine neuron survival. Thus, this body of work will add important findings to the field of Parkinson’s disease research, as I have identified a previously unknown cell-autonomous mechanism for vulnerability and resilience.