Mobile DNA Activity in Parkinson's Disease: A Locus-Specific View of Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are mobile genetic sequences derived from ancient retroviral infections. While typically silenced, their reactivation has been implicated in gene dysregulation, aging, and immune-related transcriptional pathogenesis of some neurodegenerative diseases. Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet its etiology and HERV reactivation remain poorly understood. This study investigates locus-specific HERV expression in early-stage PD, including genetic and non-genetic cases (all PD), idiopathic PD without a known genetic cause (iPD), and PD driven by leucine-rich repeat kinase 2 mutations (LRRK2 PD). We analyzed RNA-seq whole-blood samples from 492 individuals (358 all PD, 256 were iPD, 63 LRRK2 PD, and 134 healthy controls (HC)). We identified 20 significantly dysregulated HERV loci in all PD versus HC. Five HERV loci were shared with iPD analysis, and one HERV locus was shared with LRRK2 PD. Notably, these shared loci included HERV-H and ERVLE elements, indicating robust disease-associated retroviral signals independent of disease subtype. We found that genes proximal to these HERVs revealed pathways implicated in PD pathogenesis. Immune cell deconvolution showed increased neutrophil abundance and decreased resting CD4+ memory T cells proportions across the PD cohorts when compared to HC, consistent with neutrophil-lymphocyte ratio observed in previous peripheral immunity studies. Transcriptomic HERV alterations are present in whole blood across PD populations and are associated with dysregulation of fundamental cellular pathways and peripheral immune remodeling. Our findings motivate experimental validation of locus-specific HERV expression as a candidate blood-based signature with potential to inform PD neuroinflammatory and neurodegenerative processes.