Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats
Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats
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DOI：
10.1093/hmg/ddab079
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发表时间：
2021-03-22
影响因子：
3.5
通讯作者：
Shen, Lu
中科院分区：
文献类型：
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作者：
Jiao, Bin;Wang, Mengli;Shen, Lu
C9orf72 基因非编码区中的 GGGGCC 重复序列已被确定为肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆的主要遗传原因。我们之前表明，仅 GGGGCC 重复扩增就足以引起果蝇的神经变性。最近的证据表明 GGGGCC 扩展的重复序列可以修改各种基因转录组。为了确定这些基因在 GGGGCC 介导的神经毒性中的作用，我们在本研究中筛选了表达 GGGGCC 扩展重复序列的已建立的果蝇模型。我们的结果表明，DNA 拓扑异构酶 II (Top2) 基因的敲除可以特异性调节 GGGGCC 相关的眼睛神经变性。此外，Top2 的化学抑制或 siRNA 诱导的 Top2 下调可以减轻果蝇中 GGGGCC 介导的神经毒性（通过眼神经变性和运动障碍评估）。相比之下，在果蝇菌株中检测到 Top2 水平上调，此外，在表达 GGGGCC 扩展重复序列的 Neuro-2a 细胞以及 Sod1(G93A) 模型小鼠的大脑中，TOP2A 水平也上调。这表明 TOP2A 水平升高可能涉及不同 ALS 形式病理生理学的共同途径。此外，通过RNA测序，总共67个涉及细胞内信号级联、周围神经系统发育等途径的基因被确定为TOP2A调节GGGGCC介导的神经变性的潜在靶标。
GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1(G93A) model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.