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

Desirèe Valente; Clara Zannino; Stefania Scalise; Davide Bressan; Valeria Lucchino; Ermes Filomena; Giorgia Lucia Benedetto; Ida Lazzinnaro; Mariagrazia Talarico; Andrea Quattrone; Fulvio Chiacchiera; Graziano Pesole; Aldo Quattrone; Elvira Immacolata Parrotta; Giovanni Cuda

doi:10.1016/j.isci.2025.113162

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

iScience. 2025 Jul 18;28(8):113162. doi: 10.1016/j.isci.2025.113162. eCollection 2025 Aug 15.

Authors

Desirèe Valente¹, Clara Zannino¹, Stefania Scalise¹, Davide Bressan², Valeria Lucchino¹, Ermes Filomena³, Giorgia Lucia Benedetto⁴, Ida Lazzinnaro⁴, Mariagrazia Talarico⁴, Andrea Quattrone⁴, Fulvio Chiacchiera², Graziano Pesole^{3

5}, Aldo Quattrone⁶, Elvira Immacolata Parrotta⁴, Giovanni Cuda¹

Affiliations

¹ Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
² Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
³ Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy.
⁴ Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
⁵ Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, 70126 Bari, Italy.
⁶ Institute of Neurology, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.

Abstract

Progressive supranuclear Palsy-Richardson syndrome (PSP-RS) is a rare, rapidly progressive tauopathy often misdiagnosed as Parkinson's disease (PD) due to overlapping clinical features and the lack of reliable molecular biomarkers. To address this need, we generated human midbrain organoids from induced pluripotent stem cells (iPSCs) derived from individuals with sporadic PSP-RS, PD, and healthy controls (HCs), and performed longitudinal small RNA sequencing to profile microRNA (miRNA) signatures. These 3D organoids recapitulated disease-relevant pathologies, including tau hyperphosphorylation in PSP-RS and α-synuclein aggregation in PD. Transcriptomic analysis revealed dynamic, disease-specific miRNA signatures. Notably, miR-5683, miR-873-5p, miR-219b-5p, and miR-219a-2-3p were enriched in PSP-RS, while PD organoids showed increased expression of miR-1-3p and miR-133b. Differential expression analysis identified miR-5683, miR-3085-3p, and miR-124-3p as robust classifiers distinguishing PSP-RS from controls. Our findings support iPSC-derived midbrain organoids as a relevant platform for modeling atypical parkinsonian syndromes and uncovering candidate miRNA biomarkers for early and differential diagnosis.

Keywords: Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience.