Circulating Y-RNAs as New Players in Parkinson Disease and Their Associations with Clinical Measures

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss, and current therapies provide only symptomatic relief. Extracellular vesicles (EVs) have emerged as potential mediators of disease-modifying effects through the transfer of proteins, lipids, and non-coding RNAs. Y-RNAs, a conserved yet understudied class of small non-coding RNAs enriched in EVs, are implicated in fundamental cellular processes such as DNA replication, RNA stability, RNA quality control, and stress-response pathways, and may reflect disease-related cellular states, particularly given that some Y-RNA species are primate-specific. This study aimed to characterize Y-RNA expression in human neural cell models, determine how intracellular levels relate to EV-enriched extracellular profiles, and assess whether serum EV-enriched Y-RNAs show PD-associated alterations with diagnostic relevance and associations with clinical status. Methods: Human neural stem cells and malignant neural cell models were profiled for intracellular Y-RNA expression and EV-enriched extracellular Y-RNAs using EV-enriched RNA preparations. Serum samples from individuals with PD and healthy controls were analyzed to quantify circulating EV-enriched Y-RNAs. Relative Y-RNA abundance and pairwise relative Y-RNA expression measures were compared across cellular models, EV-enriched fractions, and clinical samples to identify disease-related patterns. Results: Y-RNAs displayed distinct relative expression patterns across neural cell models. EV-enriched profiles differed markedly from intracellular abundance, with consistent enrichment of RNY4 and depletion of RNY1 in EV-enriched fractions. These intracellular–extracellular differences were preserved in vesicles released under baseline conditions. In serum EV-enriched fractions, PD was associated with a specific Y-RNA signature: RNY3 related to disease presence, whereas RNY5 correlated with disease duration and severity. Pairwise relative Y-RNA expression measures also provided biologically informative signals both in cell models and patient samples. Conclusions: EV-enriched Y-RNA profiles diverge from intracellular patterns and h exploratory clinical relevance in PD, supporting their potential as markers of disease severity and contributors to disease-related molecular communication.