Astrocytes, crucial glial cells in the central nervous system, maintain brain function and neuronal health. However, understanding their role and molecular changes in Parkinson's disease (PD) is limited. To illuminate this, we employed single-nucleus profiling across four brain regions: Substantia Nigra (SN), Ventral Tegmental Area (VTA), Substantia Innominata (SI), and Hypothalamus. These regions were selected from 46 donors, each known to manifest diverse PD-related effects, using human postmortem samples. From 46 donors, including 28 sporadic PD and 18 non-PD control (NPC), we obtained 157 samples. Using paired single-nucleus RNA and ATAC sequencing, we formed one of the largest PD datasets. Integrating the samples enabled us to identify major brain cell types and further examine the astrocyte population to uncover disease-specific gene expression patterns in the substantia nigra (SN), alongside regional variability across astrocyte subpopulations in the PD brain. We found heightened stress response signatures in SN astrocytes in PD compared to NPC donors. Multiple astrocyte subpopulations enriched in SN in PD exhibited elevated expression of genes linked to a reactive astrocyte phenotype, including OSMR, SERPINA3, and C3. Additionally, this enriched cluster expressed CD44, associated with fibrous astrocytic morphology, suggesting a role in immune-mediated pathogenic processes in PD. Our ongoing research aims to integrate single-nucleus RNA-seq data with paired ATAC-seq data, establishing a multimodal signature of astrocyte molecular phenotypes in PD, with implications for therapeutic exploration.