AUTHOR=Findeiss Elisabeth , Schwarz Sigrid C. , Evsyukov Valentin , Rösler Thomas W. , Höllerhage Matthias , Chakroun Tasnim , Nykänen Niko-Petteri , Shen Yimin , Wurst Wolfgang , Kohl Michael , Tost Jörg , Höglinger Günter U. 

TITLE=Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.561086

DOI=10.3389/fcell.2021.561086

ISSN=2296-634X

ABSTRACT=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, we analyzed the miRNome two days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson’s disease, by next-generation sequencing. 
The expression levels of 23 microRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01). The in silico analysis of known target genes of these microRNAs was complemented by the inclusion of a transcriptome dataset 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 10 were found to be significantly altered upon α-synuclein overexpression, with 8 genes up- (CCND1, CCND2, CDK4, TGFB1, TP53 at P < 0.01; E2F3, MYC, SMAD3 at P < 0.05) and 2 genes downregulated (CDKN1C, MDM2 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 α-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 α-synuclein-mediated cytotoxicity.
The present findings suggest that α-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of microRNAs might offer interesting novel therapeutic targets for Parkinson’s disease.