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Findeiss, E.* ; Schwarz, S.C.* ; Evsyukov, V.* ; Roesler, T.W.* ; Hoellerhage, M.* ; Chakroun, T.* ; Nykaenen, N.* ; Shen, Y.* ; Wurst, W. ; Kohl, M.* ; Tost, J.* ; Hoeglinger, G.U.*

Comprehensive miRNome-wide profiling in a neuronal cell model of synucleinopathy implies involvement of cell cycle genes.

Front. Cell Dev. Biol. 9:561086 (2021)

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Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in alpha-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson's disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in alpha-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01; non-adjusted). The in silico analysis of known target genes of these miRNAs was complemented by the inclusion of a transcriptome dataset (BeadChip) of the same cellular system, revealing the G0/G1 cell cycle transition to be markedly enriched. Out of 124 KEGG-annotated cell cycle genes, 15 were present in the miRNA target gene dataset and six G0/G1 cell cycle genes were found to be significantly altered upon alpha-synuclein overexpression, with five genes up- (CCND1, CCND2, and CDK4 at P < 0.01; E2F3, MYC at P < 0.05) and one gene downregulated (CDKN1C at P < 0.001). Additionally, several of these altered genes are targeted by miRNAs hsa-miR-34a-5p and hsa-miR-34c-5p, which also modulate alpha-synuclein expression levels. Functional intervention by siRNA-mediated knockdown of the cell cycle gene cyclin D1 (CCND1) confirmed that silencing of cell cycle initiation is able to substantially reduce alpha-synuclein-mediated cytotoxicity. The present findings suggest that alpha-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of miRNAs might offer interesting novel therapeutic targets for PD.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Parkinson’ ; S Disease ; Alpha-synuclein ; Microrna ; Next-generation Sequencing ; Cell Cycle ; Cyclin D

ISSN (print) / ISBN 2296-634X

e-ISSN 2296-634X

Journal Frontiers in cell and developmental biology

Quellenangaben Volume: 9, Article Number: 561086

Publisher Frontiers

Publishing Place Lausanne

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)

Grants Initiative and Network Fund of the Helmholtz Association
French National Agency for Research (ANR)
Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology
Deutsche Forschungsgemeinschaft (DFG)
NOMIS foundation
Parkinson Fonds Deutschland
German Science Foundation Collaborative Research Centre (CRC)
German Federal Ministry of Education and Research (BMBF)