Integrative Transcriptomic and Systems-Level Analysis Identifies GPCR- Related Biomarkers NTSR1 and GPR161 in Parkinson’s Disease

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by progressive motor and non-motor symptoms, dopaminergic neuronal loss, and pathological α-synuclein aggregation (Kalia & Lang, 2015; Poewe et al., 2017).Despite substantial advances in understanding PD pathogenesis, the identification of reliable biomarkers for early diagnosis, prognostic stratification, and therapeutic targeting remains limited (Tolosa et al., 2021; Blauwendraat et al., 2020).G-protein-coupled receptors (GPCRs) play central roles in neurotransmission, immune regulation, and neuroinflammatory signaling, positioning them as promising candidates for biomarker discovery and therapeutic intervention in neurodegenerative diseases (Pierce et al., 2002; Insel et al., 2019).In this study, we performed an integrative transcriptomic and systems-level analysis of the publicly available GSE49036 dataset to identify GPCR-related biomarkers associated with PD (GEO Accession: GSE49036; Barrett et al., 2013).Differential expression analysis, functional enrichment, and protein–protein interaction network construction identified NTSR1 and GPR161 as key hub genes within GPCR-associated regulatory modules (Szklarczyk et al., 2019; Yu et al., 2012).Predictive nomogram modeling demonstrated the diagnostic potential of these biomarkers, while gene set enrichment analysis and consensus clustering revealed associations with DNA replication stress, GPCR signaling cascades, immune regulation, and distinct molecular PD subtypes (Subramanian et al., 2005; Wilkerson & Hayes, 2010).Single-sample gene set enrichment analysis (ssGSEA) further indicated that biomarker expression correlated with immune cell infiltration patterns, including enrichment of innate immune populations and immunosuppressive phenotypes (Hänzelmann et al., 2013; Tansey & Romero-Ramos, 2019).Integrated regulatory network analyses identified interacting miRNAs, proteins, and candidate therapeutics targeting NTSR1- and GPR161-associated pathways, suggesting potential translational and drug-repurposing applications (Ritchie et al., 2015; Karuppagounder et al., 2021).Finally, RT-qPCR validation in independent clinical samples confirmed the overexpression of NTSR1 and GPR161, supporting their biological relevance and robustness as GPCR-based biomarkers in PD (Bustin et al., 2009).Collectively, this study provides a systematic framework for GPCR-driven biomarker discovery in Parkinson’s disease, offering novel insights into disease mechanisms, neuroimmune interactions, and precision medicine strategies (Bloem et al., 2021; Insel et al., 2019).