Phosphorylation of RPS6 at Ser235 and Il-6 Release Emerge as Components of a Peripheral Inflammatory Signature in Parkinson’s Disease Manifestation
Phosphorylation of RPS6 at Ser235 and Il-6 Release Emerge as Components of a Peripheral Inflammatory Signature in Parkinson’s Disease Manifestation
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Original abstract
Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder traditionally viewed as a central nervous system disease, but increasing evidence indicates that peripheral immune alterations contribute to disease pathophysiology. Moreover, the molecular features of peripheral blood mononuclear cells (PBMCs) in idiopathic and genetic forms of PD remain incompletely understood. Methods We performed mass spectrometry–based proteomic and phosphoproteomic profiling of PBMCs obtained from healthy controls, patients with idiopathic PD (iPD), and carriers of the LRRK2 G2019S mutation with (L2PD) or without (L2NMC) motor manifestations. Key findings were validated using biochemical and functional approaches in patient-derived PBMC cultures, including assessment of interleukin-6 (IL-6) secretion, and by evaluating downstream signaling effects in primary mouse astrocytes exposed to PBMC-conditioned media. Results Distinct proteomic and phosphoproteomic patterns were observed across PD groups, with consistent enrichment of ribosome-related pathways in manifesting disease. Phosphorylation of ribosomal protein S6 at Ser235 (pSer235-RPS6) was increased in iPD and LRRK2-associated PD but not in non-manifesting mutation carriers. pSer235-RPS6 levels correlated with clinical severity across multiple Unified Parkinson’s Disease Rating Scale domains. PBMCs derived from patients with iPD released markedly higher levels of IL-6 compared with other groups. Moreover, conditioned media from iPD PBMC cultures induced RPS6 phosphorylation in primary astrocytes, supporting a functional link between peripheral immune signaling and inflammatory glial responses. Conclusions These findings define a disease-associated peripheral immune signaling state in Parkinson’s disease, characterized by coordinated activation of translational and inflammatory pathways. Phosphorylation of ribosomal protein S6 at Ser235 and increased IL-6 release distinguish manifest from non-manifest disease across idiopathic and LRRK2-associated PD, correlate with clinical severity, and occur independently of direct LRRK2 kinase activity. Together, these results support a functional link between peripheral immune dysregulation and central nervous system–relevant signaling, highlighting peripheral translational control as a biologically meaningful and accessible marker of disease manifestation with translational relevance for patient stratification and monitoring of phenoconversion.