Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects motor and non-motor functions. However, the molecular mechanisms underlying PD remain unclear, and effective treatments are limited. Recent advances in single-cell RNA sequencing provide new insights into PD. Therefore, this study aims to explore cellular and molecular changes in PD using high-dimensional transcriptomic analysis.

Methods: This study analyzed single-cell RNA sequencing data (GSE157783) and gene expression data from the substantia nigra (GSE20292 and GSE20333). Dimensionality reduction and clustering identified 17 cell populations, and differential gene expression analysis identified signal transducer and activator of transcription 6 (STAT6) as a key regulator, which was further examined in PD model cells.

Results: Single-cell analysis revealed significant differences (p < 0.05) in specific cell populations between PD and control samples. STAT6 was identified as a key gene upregulated in both single-cell and tissue-level datasets. In vitro experiments showed that the overexpression of STAT6 in PD model cells reduced apoptosis and α-synuclein aggregation, while improving cell viability and migration (p < 0.05) by activating the mechanistic target of rapamycin (mTOR) signaling pathway. Conversely, STAT6 knockdown significantly increased apoptosis and aggregation of α-synuclein, and reduced cell viability and migration (p < 0.05). Additionally, the neuroprotective effect of STAT6-overexpression was significantly inhibited by the mTOR inhibitor, Rapamycin (p < 0.05).

Conclusion: This study highlights STAT6 as a key molecular regulator in PD, suggesting that targeting the STAT6-mTOR axis could be a promising therapeutic strategy in managing this disease. Future research should focus on further elucidating the role of STAT6 in the progression of PD and evaluating its therapeutic potential.