cGAS-STING Pathway Validation Study in Parkinson's Disease

SUMMARY

# cGAS-STING Pathway Validation Study in Parkinson's Disease ## Background and Rationale This pivotal clinical validation study investigates the cGAS-STING innate immune pathway as a fundamental driver of dopaminergic neurodegeneration in Parkinson's disease. The cytosolic DNA sensor cGAS and its downstream effector STING have emerged as critical mediators of sterile inflammation in neurodegenerative diseases. In PD, mitochondrial dysfunction and α-synuclein aggregation can release cytosolic DNA

METHODOLOGY NOTES

**Phase 1: Patient Recruitment and Baseline Assessment (Months 1-6)** • Recruit 120 PD patients (Hoehn & Yahr stages 1-3) and 60 age-matched healthy controls • Obtain informed consent and perform comprehensive neurological assessments using MDS-UPDRS III • Collect CSF samples (15mL) via lumbar puncture and blood samples (50mL) for biomarker analysis • Perform DaTscan imaging to confirm dopaminergic denervation • Conduct cognitive assessments using MoCA and neuropsychological battery **Phase 2: Biomarker Analysis and Pathway Validation (Months 4-8)** • Measure cGAS and STING protein levels in CSF using ELISA (sensitivity 0.1 ng/mL) • Quantify cGAMP levels in CSF and plasma using LC-MS/MS (LOD 0.05 nM) • Analyze inflammatory cytokines (IL-1β, TNF-α, IL-6, IFN-β) using multiplex immunoassay • Perform peripheral blood mononuclear cell isolation and measure cGAS-STING pathway gene expression via qRT-PCR • Conduct immunohistochemistry on post-mortem brain tissue (n=20 PD, n=10 controls) for