Longitudinal Systemic Transcriptomic Profiling and Neuropathological Deposition of Neutrophil Extracellular Traps in...

Altered immune responses including increased neutrophils have been reported in Parkinson's disease (PD); however, the role of neutrophil extracellular traps (NETs) remains unclear.

The aim of this study was to evaluate the contribution of NETs to the systemic immunity and central nervous system (CNS) in PD pathogenesis.

Transcriptomic analysis from the Parkinson's Progression Markers Initiative (PPMI) cohort was performed. Serum NETs were measured by myeloperoxidase (MPO)-DNA and citrullinated histone H3 (CitH3)-DNA complexes using enzyme-linked immunosorbent assay (ELISA). In addition, NET structures in postmortem brains of individuals with PD and multiple system atrophy (MSA) were quantified using ELISA and visualized by confocal microscopy.

Differential expression gene analysis showed significant systemic upregulation of PADI4 expression, which encodes the NET-priming enzyme peptidylarginine deiminase 4, in patients with PD compared with control subjects. In the regional cross-sectional cohort, serum MPO-DNA complexes were reduced in patients with PD compared with control subjects and showed a graded reduction with disease severity; this reduction was independently replicated using a CitH3-DNA ELISA. In contrast, NET structures were markedly increased in postmortem brain tissues from individuals with PD and MSA compared with control subjects. Confocal imaging further confirmed the presence of NETs in the PD brain cortex, with an increased density in the substantia nigra and in close proximity to Lewy bodies.

These findings demonstrated systemic priming of NET-associated pathways accompanied by reduced circulating NET complexes in PD, alongside substantial NETs deposition within the CNS. Together, these observations identify the PADI4-NET axis as a candidate immune feature of PD that warrants further mechanistic investigation. © 2026 International Parkinson and Movement Disorder Society.