Objective: To investigate whether miRNA expression alterations occur in iPSC-derived DAn from sporadic PD (sPD) as well as monogenic LRRK2-associated PD patients.

Background: MicroRNA (miRNA) deregulation in blood has been associated with Parkinson disease (PD) but its role in the progression of disease is not known. We screened miRNAs expression in dopaminergic neurons (DAn) from PD patients generated by somatic cell reprogramming and induced pluripotent stem cells (iPSC) differentiation.

Methods: We quantified the expression of 377 miRNAs by using microRNA array cards in induced DAn from three sporadic PD patients (sPD), three monogenic LRRK2-associated PD patients (L2PD) (total six PD), and four healthy controls as to identify differentially expressed miRNA (DEmiR) associated with PD. We overlapped DEmiR expression data with transcriptomic data from the same samples as to evaluate potential regulatory implications of identified DEmiR.

Results: We found statistically significant differential expression of ten miRNA in PD of which five were up-regulated and five down-regulated. Expression changes were similar in sPD and L2PD. Identified DEmiR are involved among others in DAn survival and maduration. More specifically, up-regulation of two specific DEmiR is associated with the down-regulation of the transcription factors FOXA1 and NR3C1, which are related to epigenetic alterations in PD DAn, namely DNA hypermethylation of enhancer elements. Integrative analysis revealed significant correlations between miRNA/mRNA expression supporting a role of miRNAs in regulating gene expression.

Conclusions: In summary, our results indicate that the same miRNA changes are associated with both monogenic L2PD and sPD in our model of iPSC–DAn and co-occur with epigenetic changes in DAn from PD patients. Overall, this study shows that a systems biology-based approach can be suitable to investigate molecular changes of complex multifactorial neurodegenerative diseases such as PD.

References: Fernandez-Santiago, R. et al. Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. EMBO Mol Med 7, 1529-1546, doi:emmm.201505439 [pii]10.15252/emmm.201505439 (2015).Liu, Y. et al. Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson’s Disease. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 40, 18-26, doi:10.1159/000452521 (2016). Sales, G. et al. MAGIA, a web-based tool for miRNA and Genes Integrated Analysis. Nucleic acids research 38, W352-359, doi:10.1093/nar/gkq423 (2010). Sanchez-Danes, A. et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med 4, 380-395, doi:10.1002/emmm.201200215 (2012). Wu, J. et al. Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proceedings of the Nationa l Academy of Sciences of the United States of America 111, E2851-2857, doi:10.1073/pnas.1407777111 (2014).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/microrna-expression-misregulation-in-ipsc-derived-dopaminergic-neurons-from-sporadic-and-lrrk2-associated-parkinson-disease-patients/