Down regulation of DNA topoisomerase II beta exerts neurodegeneration like effect through Rho GTPases in cellular model of Parkinson's disease by Down regulating tyrosine hydroxylase

Initiating the transcriptional activation of neuronal genes, DNA topoisomerase II beta (topo II beta) has a crucial role in neural differentiation and brain development. Inhibition of topo II beta activity causes shorter axons and deteriorated neuronal connections common in neurodegenerative diseases. We previously reported that topo II beta silencing could give rise to neurodegeneration through dysregulation of Rho GTPases and may contribute to pathogenesis of neurodegenerative diseases. Although there are several studies available proposing a link between Parkinson's Disease (PD) and Rho GTPases, there have been no reports analyzing the topo II beta-dependent association of PD and Rho GTPases. Here, for the first time, we identified that topo II beta has a regulatory role on Rho GTPases contributing to PD-like pathology. We analyzed the association between topo II beta and PD by comparing topo II beta expression levels of Retinoic Acid (RA) and Brain-derived neutrophic factor (BDNF) induced and MPP+-intoxicated SH-SY5Y cells used as an in vitro PD model. While both mRNA and protein levels of topo II beta increase in neural differentiated cells, a significant decrease is detected in the PD model. Additionally, silencing of topo II beta by specific siRNAs caused phenotypic alterations like deteriorated neural connections and transcriptional regulations such as upregulation of RhoA and downregulation of Cdc42, Rac1, and tyrosine hydroxylase gene expressions. Our results suggest that topo II beta downregulation may cause neurodegeneration through dysregulation of Rho-GTPases leading to PD-like pathology.