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. 2025 May;15(3):495-511.
doi: 10.1177/1877718X251331930. Epub 2025 Apr 4.

Identification of a circRNA-miRNA-mRNA interactome associated with Parkinson's disease progression

Lisa Shrestha  1 , André Leier  1   2
Affiliations
Free article

Identification of a circRNA-miRNA-mRNA interactome associated with Parkinson's disease progression

Lisa Shrestha et al. J Parkinsons Dis. 2025 May.
Free article

Abstract

BackgroundCircular RNAs (circRNAs) constitute a distinctive subclass of RNAs that are known for their regulatory roles in fundamental cellular processes. Due to their increased stability and ubiquitous expression, circular RNAs have been widely studied as potential molecular targets in various diseases, including neurodegenerative diseases. While several studies have found differentially expressed circRNAs associated with Parkinson's disease (PD), none has looked specifically into PD progression.ObjectiveTo elucidate the role of circRNAs in the progression of PD by identifying dysregulated circRNAs associated with PD progression and to pinpoint potential downstream miRNAs and associated differentially expressed gene targets.MethodsIn this study, we have utilized large-scale, longitudinal, and deep RNA-seq data from two independent cohorts, namely the Parkinson's Progression Marker Initiative (PPMI) and the Parkinson's Disease Biomarker Program (PDBP), to characterize circRNA expression in patients of early PD stage.ResultsWe identified six circRNAs significantly differentially expressed in whole blood samples obtained from PD patients over time. Additionally, we were able to map a competing endogenous RNA (ceRNA) network with potential downstream miRNA-mRNA targets and, with the help of co-expression analysis, to identify genes associated with PD progression. Our findings provide compelling evidence for a dysregulated circRNA interactome as an indicator of PD progression, with changes in the expression of these circRNAs and downstream gene targets being significantly associated with changes in UPDRS III scores in PD patients.ConclusionsOur results strongly indicate the association of circular RNAs with PD progression and emphasize its significance as a critical molecular marker.

Keywords: Parkinson's disease biomarker program; Parkinson's disease progression; Parkinson's progression marker initiative; UPDRS III (On); circular RNA; co-expression networks; competing endogenous RNA; molecular biomarker; sparse partial correlation ON gene expression; weighted gene correlational network analysis.

Plain language summary

Circular RNAs (circRNAs) are stable RNA molecules, some of which have been linked to cellular processes involved in neurodegenerative diseases. Their role in Parkinson's disease (PD) progression has not been well explored. In this study, we analyzed blood samples from 168 people with early-stage PD and 76 healthy individuals using RNA sequencing data from two large research programs, PPMI and PDBP. We identified six circRNAs that were significantly dysregulated over time in early-stage PD patients from both cohorts. Furthermore, changes in expression levels of these circRNAs could help predict disease progression based on UPDRS III (On) scores with reasonable accuracy (AUC of 0.693 [0.594–0.792]). We also explored how these circRNAs might influence gene regulation through microRNA (miRNA) sponging, identifying a circRNA-miRNA-mRNA network linked to PD-associated pathways. Our findings suggest that these circRNAs could serve as potential biomarkers for tracking PD progression and provide insights into its molecular mechanisms.

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Conflict of interest statement

Conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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