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Down regulation of DNA topoisomerase IIβ exerts neurodegeneration like effect through Rho GTPases in cellular model of Parkinson’s disease by Down regulating tyrosine hydroxylase
Neurological Research ( IF 1.9 ) Pub Date : 2021-01-05 , DOI: 10.1080/01616412.2020.1867949
Kiyak Bercem Yeman 1 , Sevim Isik 2
Affiliation  

ABSTRACT

Initiating the transcriptional activation of neuronal genes, DNA topoisomerase IIβ (topo IIβ) has a crucial role in neural differentiation and brain development. Inhibition of topo IIβ activity causes shorter axons and deteriorated neuronal connections common in neurodegenerative diseases. We previously reported that topo IIβ 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 IIβ-dependent association of PD and Rho GTPases. Here, for the first time, we identified that topo IIβ has a regulatory role on Rho GTPases contributing to PD-like pathology. We analyzed the association between topo IIβ and PD by comparing topo IIβ 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 IIβ increase in neural differentiated cells, a significant decrease is detected in the PD model. Additionally, silencing of topo IIβ 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 IIβ downregulation may cause neurodegeneration through dysregulation of Rho-GTPases leading to PD-like pathology.



中文翻译:

DNA拓扑异构酶IIβ的下调通过下调酪氨酸羟化酶在帕金森病细胞模型中通过Rho GTP酶发挥神经变性样作用

摘要

DNA 拓扑异构酶 IIβ (topo IIβ) 启动神经元基因的转录激活,在神经分化和大脑发育中起着至关重要的作用。topo IIβ 活性的抑制导致神经退行性疾病中常见的轴突缩短和神经元连接恶化。我们之前报道过,拓扑 IIβ 沉默可能通过 Rho GTP 酶的失调引起神经变性,并可能导致神经退行性疾病的发病机制。尽管有几项研究提出了帕金森病 (PD) 和 Rho GTP 酶之间的联系,但没有报告分析 PD 和 Rho GTP 酶的拓扑 IIβ 依赖性关联。在这里,我们第一次发现拓扑 IIβ 对 Rho GTP 酶具有调节作用,从而导致 PD 样病理。体外PD 模型。虽然神经分化细胞中 topo IIβ 的 mRNA 和蛋白质水平均增加,但在 PD 模型中检测到显着降低。此外,特定 siRNA 对 topo IIβ 的沉默会导致表型改变,如神经连接恶化和转录调控,如 RhoA 上调和 Cdc42、Rac1 和酪氨酸羟化酶基因表达下调。我们的结果表明,topo IIβ 下调可能通过 Rho-GTPase 的失调导致神经变性,从而导致 PD 样病理。

更新日期:2021-01-05
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