Overexpression of C9orf72 exacerbates Aβ25-35-induced oxidative stress and apoptosis in PC12 cells
Overexpression of C9orf72 exacerbates Aβ25-35-induced oxidative stress and apoptosis in PC12 cells
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C9orf72 的过度表达加剧 Aβ25-35 诱导的 PC12 细胞氧化应激和细胞凋亡
DOI：
10.55782/ane-2022-007
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发表时间：
2022-01-01
影响因子：
1.4
通讯作者：
Lou, Jiyu
中科院分区：
文献类型：
--
作者：
Chen, Jing;Zhang, Mingming;Lou, Jiyu
阿尔茨海默病（AD）是最常见的神经退行性疾病，表现为记忆丧失和空间定向障碍。目前还没有有效的治疗AD的方法。9号染色体开放阅读框72（C9 orf 72）基因的缺失与多种神经退行性疾病有关。然而，其在AD中的内在作用仍有待阐明。在此，我们发现A β（25-35）在mRNA和蛋白水平上增加了PC 12细胞中C9 orf 72的表达。在A β（25-35）处理的PC 12细胞中，C9 orf 72过表达诱导异常浓缩和破碎的核和凋亡，以及显著增强的活性氧（ROS）水平。从机制上讲，A β（25-35）诱导的超氧化物歧化酶活性降低被C9 orf 72过表达增强，相反，这增加了丙二醛含量。一致地，进一步的凋亡分析揭示了A β（25-35）处理显著下调Bcl-2和Bcl-xL表达，并增强caspase-3的切割，所有这些都被C9 orf 72过表达加剧。此外，AD病理学的另一个标志tau磷酸化由A β（25-35）诱导，并且通过C9 orf 72过表达显著增强。我们的数据表明，C9 orf 72在细胞内ROS信号传导和A β（25-35）诱导的AD神经元凋亡中起重要作用。这些发现为深入了解C9 orf 72在许多相关神经退行性疾病发病机制中的功能提供了依据，并为潜在的治疗干预提供了基础。
Alzheimer's disease (AD) is the most common neurodegenerative disease and is manifested by memory loss and spatial disorientation. There is currently no effective treatment for AD. Abnormalities of the chromosome 9 open reading frame 72 (C9orf72) gene have been associated with various neurodegenerative diseases. However, its intrinsic roles in AD remain to be elucidated. Here we found that A beta(25-35) increased the expression of C9orf72 in PC12 cells at both mRNA and protein levels. In A beta(25-35)-treated PC12 cells, C9orf72 overexpression induced an abnormally condensed and fragmented nucleus and apoptosis, as well as significantly enhanced reactive oxygen species (ROS) levels. Mechanistically, an A beta(25-35)-induced decrease of superoxide dismutase activity was augmented by C9orf72 overexpression, which in contrast increased malondialdehyde content. Consistently, further apoptotic analysis revealed significant downregulation of Bcl-2 and Bcl-xL expression and enhanced cleavage of caspase-3 with A beta(25-35) treatment, all of which were exacerbated by C9orf72 overexpression. In addition, tau phosphorylation, another hallmark of AD pathology, was induced by A beta(25-35) and was remarkably enhanced by C9orf72 overexpression. Our data indicate that C9orf72 plays important roles in intracellular ROS signaling and A beta(25-35)-induced neuronal apoptosis in AD. These findings provide insights into C9orf72 function in the pathogenesis of many related neurodegenerative diseases and provide a basis for potential therapeutic interventions.