Objective: To identify small non-coding RNAs (sncRNAs) signatures in multiple system atrophy (MSA) and elucidate their functional mechanisms within patient-derived induced pluripotent stem cell-differentiated oligodendrocytes (iPSC-OLs).

Background: The potentials of sncRNAs, particularly microRNAs (miRNAs) of differentiating MSA from Parkinson’s disease (PD) and healthy controls (HCs) remains incompletely characterized.

Method: We conducted a two-stage study involving discovery and validation cohorts recruited from the Department of Neurology, National Taiwan University Hospital. Non-targeted next-generation sequencing (NGS)-based RNAseq was employed to profile differentially expressed (DE) circulating sncRNAs, with validation focused on sncRNAs consistently present across both cohorts. MSA-associated sncRNAs (MSA-miRs) were individually validated in iPSC-OLs derived from one MSA patient and one HC.

Results: A total of 160 participants were enrolled: discovery cohort (10 MSA, 41 PD, 17 HC) and validation cohort (38 MSA, 38 PD, 16 HC). We identified a distinct MSA-miR signature comprising five upregulated and eight downregulated miRNAs, predominantly implicated in synaptic signaling and synaptogenesis by pathway enrichment analysis. Three downregulated MSA-miRs are detectable in human cerebrospinal fluid (CSF) and enriched in brain tissue. Notably, miR-181b-5p, a miR enriched in neurons, was both up-regulated in plasma of patients with MSA and PD (Figure 1) and in the early stage of MSA-iPSC cells during the transition phase from neural stem cells to oligodendrocyte progenitor cells (Figure 2). The functional roles of miR-181b-5p-targeted genes were involved in neurotrophin signaling pathway, axon guidance, and alpha-synuclein-related MAPK signaling pathway. Although miR-181b-5p didn’t reveal significant differences in iPSCs based on miRNAseq, other members of the miR-181 family, including miR-181a-3p, miR-181b-2-3p, miR-181c-3p, miR-181c-5p, and miR-181d-5p, exhibited 3-5 folds of upregulation.

Conclusion: A novel panel of circulating MSA-miRs offer a potential biomarker approach but also provide mechanistic insights into MSA pathogenesis. Translational investigations focusing on miR-181b-5p and its family miRNAs within the iPSC-OL model represent a crucial next step in understanding this complex neurodegenerative disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/microrna-landscape-of-multiple-system-atrophy-insights-from-plasma-and-patient-derived-induced-pluripotent-stem-cell-models/