Advances in sex-specific single-cell transcriptomic profiling in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of misfolded alpha-synuclein. While traditional bulk RNA-sequencing has provided valuable insights into PD pathology, it fails to capture the complex cellular heterogeneity of the human brain. Advances in single-cell transcriptomics have revolutionized our ability to dissect this complexity, enabling the identification of rare, disease-associated cell populations, or the inference of dysregulated intercellular communication networks. In this review, we discuss methodological and analytical frameworks of single-cell RNA-sequencing and summarize key findings from recent studies using single-cell RNA-sequencing that advance our understanding of PD. We highlight how single-cell transcriptomics has refined our understanding of neuronal vulnerability and revealed critical contributions of non-neuronal cells, particularly microglia and oligodendrocytes, to disease pathology in both human postmortem tissue and experimental model systems. Finally, we discuss emerging evidence for sex-specific molecular alterations in PD and emphasize the importance of sex-aware study design and analysis in future single-cell PD research.