Abstract
Mounting evidence suggests a significant correlation between depressive disorders and neurodegenerative conditions, encompassing Alzheimer's disease and Parkinson's disease (PD). Depression represents a substantial non-motor manifestation frequently identified in individuals with PD, posing a significant threat to patients' overall well-being and necessitating the implementation of effective management strategies. Despite its high prevalence, impacting over 40% of PD patients, the precise cellular and molecular mechanisms underlying depression and its relationship to dopaminergic system degeneration remain largely ambiguous. In this study, we presented our findings demonstrating distinct characteristics of cortical astrocytes in PD patients compared to reactivated glial cells in the substantia nigra. We identified a subset of differentially expressed genes associated with depressive disorders from PD-associated cortical astrocytes. Furthermore, we uncovered the potential involvement of the hypoxia signaling in driving cortical astrocytic dysfunctions. Through a comprehensive investigation utilizing transcriptome and chromatin accessibility analyses on cultured human astrocytes, we revealed that hypoxic treatment could induce similar expression changes observed in cortex from PD patients. Additionally, we provided evidence that activation of the HIF-1 signaling pathway suppressed the expression of key components of mitochondrial ribosomes and electron transport chain proteins COX2 and CYTB, resulting in abnormal mitochondrial membrane potential. Our results underscore the potential impact of glial metabolic abnormalities on the development of depressive disorders associated with Parkinson's disease.