Abstract
Parkinson¿s disease (PD) is a complex neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of ¿-synuclein aggregates. Despite extensive research, the molecular pathogenesis ¿particularly in idiopathic cases, which represent the majority¿ remains incompletely understood. Traditional approaches such as bulk RNA sequencing have offered insights but often mask cell-type-specific signals and typically focus on the substantia nigra, potentially overlooking relevant mechanisms in other brain regions.
To address these limitations, we analyzed a large-scale single-nucleus RNA sequencing dataset from the Accelerating Medicines Partnership Parkinson¿s Disease (AMP-PD) program, comprising 2.4 million nuclei from five brain regions in 97 post-mortem individuals (73 cases with PD and 24 healthy controls). This represents the most comprehensive single-cell dataset for Parkinson¿s disease assembled to date.
After preprocessing and batch-correcting the dataset, we applied semi-automated cell type annotation via label transfer from the most extensive human brain reference atlas currently available. We identified 18 distinct cell types across regions, capturing cellular heterogeneity with high resolution. Differential abundance analysis revealed a marked increase in astrocytes and microglia in PD samples compared to controls, reinforcing growing evidence of glial involvement in disease progression. In addition, ongoing region-specific differential expression analyses are uncovering localized molecular changes that may further elucidate PD pathogenesis.
Together, our findings highlight the role of glial cells in PD and emphasize the need to examine both region- and cell-type-specific mechanisms to fully understand the neurodegenerative processes underlying Parkinson¿s disease.
