circ_0005654 as a Sponge of the miR-588 Dual Pathway to Promote α-Synuclein Expression.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the abnormal aggregation of α-synuclein (α-Syn), involving complex regulatory networks where the roles and mechanisms of circular RNAs (circRNAs) remain underexplored. Through RNA sequencing analysis, we identified significant upregulation of circ_0005654 (derived from the PRDM5 gene) in PD patients. Functional studies demonstrated that circ_0005654 overexpression promotes α-Syn accumulation through a dual regulatory mechanism: (1) direct enhancement of its transcriptional/translational activation of α-Syn and (2) indirect suppression of autophagic clearance via miR-588 sequestration-mediated inhibition of the p62-dependent autophagy pathway. Specifically, circ_0005654 functions as a molecular sponge for miR-588, thereby coordinately enhancing α-Syn synthesis while impairing its degradation. This study not only establishes the functional role of circRNAs in PD pathogenesis but also elucidates circ_0005654 as a promising therapeutic candidate for targeted modulation of α-Syn aggregation.