A single-cell meta-analysis evidences transposable element dysregulation in sex-based differences in Parkinson's disease.

Transposable elements (TEs) (mobile genetic elements comprising ~45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood. Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 patients, generating cell-type-resolved atlas of TE dysregulation in PD. We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes. Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons. Correlation and genomic proximity also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination. Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.