0801 Divergent Dopamine-Iron Molecular Signatures Differentiate Restless Legs Syndrome from Parkinson’s Disease

Abstract Introduction Restless legs syndrome (RLS) and Parkinson’s disease (PD) both respond to dopaminergic therapies and may co-occur clinically, yet it remains uncertain whether they share common biological substrates or represent distinct pathophysiological entities. In particular, dopamine handling and iron metabolism appear oppositely altered in the two conditions. We performed a targeted transcriptomic comparison to clarify similarities and differences in dopamine- and iron-related molecular pathways. Methods Peripheral blood RNA sequencing was performed in patients with idiopathic RLS (n = 17) and PD (n = 63), diagnosed according to international criteria. After quality control and filtering, 23,331 expressed genes were analyzed. Differential expression analysis between groups was conducted adjusting for age and sex, using a threshold of adjusted p ≤ 0.01 and |fold change| ≥ 2.5. Genes involved in dopamine metabolism/signaling and iron transport, utilization, and ferroptosis were examined in detail. Results A total of 2,925 transcripts were differentially expressed between RLS and PD. In the dopamine axis, RLS showed upregulation of catechol-O-methyltransferase-related genes (COMTD1, LRTOMT) and downregulation of PTS, a key enzyme for tetrahydrobiopterin synthesis, suggesting increased dopamine turnover with limited synthetic capacity. In the iron axis, RLS displayed upregulation of genes promoting iron export and mitochondrial/heme utilization (SLC40A1, HEPH, SLC25A37/39, ALAS2, FECH, GLRX5) and downregulation of TFRC, consistent with an iron-mobilization program under conditions of restricted availability. These patterns contrasted with PD, a disorder characterized by nigrostriatal neurodegeneration and brain iron accumulation. Conclusion RLS and PD exhibit divergent transcriptomic signatures within the dopamine-iron regulatory network, reflecting functional dopaminergic dysregulation with brain iron deficiency in RLS versus structural neurodegeneration with iron overload in PD. These findings support distinct biological mechanisms underlying the clinical features and have implications for biomarker development and targeted therapies. Support (if any) This study was supported by institutional research funds.