Abstract

Background and Objectives: Hypoxia-inducible factor-1 alpha (HIF-1α) is a central regulator of cellular responses to hypoxia and has been implicated in the pathophysiology of several neurological disorders. Parkinson’s disease (PD) and restless legs syndrome (RLS) have both been associated with alterations in oxygen sensing, mitochondrial dysfunction, and disturbances in amino acid metabolism; however, the relationship between HIF-1α and amino acid metabolic pathways in these disorders remains incompletely understood. The present study investigated circulating HIF-1α concentrations and amino acid metabolite profiles in patients with PD and RLS. Materials and Methods: In this cross-sectional study, 55 participants were enrolled, including 30 healthy controls, 12 patients with PD, and 13 patients with RLS. Plasma HIF-1α concentrations were measured using an enzyme-linked immunosorbent assay, and amino acid metabolites were quantified by liquid chromatography–tandem mass spectrometry. Group comparisons were performed using non-parametric methods with FDR correction. Age- and sex-adjusted regression analyses, correlation analyses, and PCA were used to assess metabolic relationships and group discrimination. Results: Significant group differences were observed for HIF-1α and multiple amino acid metabolites. Compared with controls, both PD and RLS patients exhibited significantly higher concentrations of arginine, citrulline, homocitrulline, and HIF-1α, whereas ornithine concentrations were significantly lower. Arginine demonstrated the largest effect size among all biomarkers (ε2 = 0.713). HIF-1α concentrations showed a progressive increase across groups, with the highest levels observed in RLS. Correlation analyses revealed strong positive associations of HIF-1α with arginine, citrulline, and homocitrulline, and an inverse association with ornithine. These findings remained significant after adjustment for age and sex. PCA showed clear separation between controls and disease groups. Conclusions: PD and RLS are characterized by a shared metabolic signature involving elevated HIF-1α, increased arginine-pathway metabolites, and reduced ornithine concentrations. The detected associations between HIF-1α and metabolites of the arginine–citrulline–ornithine pathway suggest a potential link between hypoxia-related signaling and metabolic dysregulation in both disorders. These findings support further investigation of HIF-1α-associated metabolic pathways as potential biomarkers and therapeutic targets in neurodegenerative and movement disorders.

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