Distinct microRNA signatures define sporadic PSP-RS and PD in patient-derived midbrain organoids

Progressive Supranuclear Palsy–Richardson Syndrome (PSP-RS) is a rare, rapidly progressive neurodegenerative tauopathy frequently misdiagnosed as Parkinson’s Disease (PD) due to overlapping clinical features. The lack of reliable molecular biomarkers for early and differential diagnosis presents a major clinical challenge. To address this, we developed human midbrain organoids from induced pluripotent stem cells (iPSCs) derived from patients with sporadic PSP-RS, PD, and healthy controls (HCs), and profiled microRNA (miRNA) expression dynamics using small RNA sequencing. These 3D organoid models faithfully recapitulate key pathological hallmarks, including tau hyperphosphorylation in PSP-RS and Lewy body–like α-synuclein inclusions in PD. Our analysis revealed temporally dynamic, disease-specific miRNA signatures: miR-5683, miR-873-5p, miR-219b-5p, and miR-219a-2- 3p were selectively upregulated in PSP-RS, whereas PD organoids showed increased levels of miR-1-3p, miR-133b, miR-10b-5p, and miR-199a-5p. Additionally, miR-5683, miR-3085- 3p, miR-138-2-3p, and miR-124-3p emerged as key discriminators between PSP-RS and HCs. These findings highlight the utility of iPSC-derived midbrain organoids as a translationally relevant platform to uncover disease-specific regulatory networks and identify candidate miRNA biomarkers for atypical parkinsonian syndromes. small RNAseq was carried out to characterize dynamic changes in miRNA expression at 60, 90, and 120 days. The samples are from iPSCs-derived midbrain organoids in three conditions: sporadic Progressive Supranuclear Palsy–Richardson Syndrome (PSP-RS), parkinson disease (PD), and healthy controls (HCs). Three replicates per condition for each time point (60,90,120d) are present (total of 27).