Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease

Monocytes are increasingly implicated in Parkinson's disease (PD) pathogenesis, with idiopathic cases showing mitochondrial and lysosomal dysfunction. However, the impact of PD-associated mutations on monocytes remains unclear. To address this, we investigated transcriptomic and functional disturbances in peripheral monocytes from patients with GBA1- and LRRK2-associated PD and idiopathic PD. Transcriptomic data revealed shared and mutation-specific signatures, including those related to immune dysregulation, and consistent defects in lysosomal, proteasomal and mitochondrial pathways. Network and pathway analyses further uncovered downregulation in protein translation and enrichment of integrated stress response (ISR) signatures, alongside aberrant expression of genes linked to ER stress, mitophagy and type-I interferon signaling. Protein levels of heat-shock proteins and ISR effectors were elevated at baseline and following α-synuclein exposure, consistent with impaired proteostasis. Live-cell assays demonstrated defects in lysosomal function, mitochondrial dynamics, and phagocytosis, most pronounced in GBA1- and LRRK2-associated PD but evident across all PD groups. Together, these findings define a PD-associated myeloid state of immunodegeneration, marked by impaired clearance, proteostasis failure, and mitochondrial dysfunction across genetic and idiopathic PD.