Unraveling the role of non-coding RNAs in Parkinson's disease: Molecular mechanisms and therapeutic insights.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta and pathological accumulation of α-synuclein in Lewy bodies. In this process, a set of non-coding RNAs including miRNAs, lncRNAs, and circRNAs form key regulatory layers in the pathogenesis of the disease and directly affect α-synuclein homeostasis, mitochondrial function, oxidative stress, neuroinflammation, autophagy, and proteostasis. Dysregulation of miRNAs targets neurosensitive pathways; miR-7 and miR-153 inhibit SNCA translation, miR-27a/b and miR-103a-3p regulate the PINK1/Parkin axis in mitophagy, and miR-155, together with miR-135b, modulate the regulation of the NF-κB/NLRP3 dependent inflammasome. On a broader level, lncRNAs with destructive roles such as NEAT1, HOTAIR, MALAT1, SNHG1, UCA1 and GAS5 increase α-synuclein accumulation and impair autophagy through ceRNA and chromatin remodeling mechanisms. On the other hand, circRNAs with their stable circular structure alter posttranslational regulation through miRNA sponging; such that circSNCA, CDR1as and circSLC8A1 enhance α-synuclein load, impair mitophagy and exacerbate oxidative stress, while circDLGAP4 has a neuroprotective function. Data from single-cell sequencing and multi-omics reveal cell-specific patterns of ncRNA dysregulation in microglia, astrocytes and dopaminergic neurons, highlighting their importance in early diagnosis, molecular stratification of patients and development of targeted therapies.