Streptozotocin-Induced Astrocyte Mitochondrial Dysfunction Is Ameliorated by FTO Inhibitor MO-I-500
Streptozotocin-Induced Astrocyte Mitochondrial Dysfunction Is Ameliorated by FTO Inhibitor MO-I-500
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DOI：
10.1021/acschemneuro.1c00063
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发表时间：
2021-09-07
影响因子：
5
通讯作者：
Novotny, Jiri
中科院分区：
文献类型：
--
作者：
Cockova, Zuzana;Honc, Ondrej;Novotny, Jiri
阿尔茨海默病（AD）是最常见的痴呆形式，其发病机制尚不清楚。在过去的几年中，已经积累的证据表明，扰动的大脑生物能量学和神经炎症可能会损害认知功能，并在AD发作之前，神经胶质细胞的功能受损可能有助于疾病的发展。最近，N6-甲基腺苷（m6 A）修饰的RNA已被牵连在不同的过程在大脑中的调节，并在神经退行性变中发挥潜在的作用。在本研究中，我们研究了在人星形细胞瘤CCF-STTG 1细胞中链脲佐菌素（STZ）AD模型中m6 A机械酶的潜在作用。我们观察到STZ处理的星形胶质细胞表达显著更高水平的m6 A脱甲基酶脂肪质量和肥胖相关蛋白（FTO）和m6 A阅读器YTHDF 1（YTH结构域包含家族蛋白1）。我们的实验表明，MO-I-500，一种新的药理学抑制剂FTO，可以大大减少STZ的不良反应。FTO的抑制增强了暴露于STZ的细胞的存活，并抑制了氧化应激、细胞凋亡、胶质细胞酸性蛋白表达升高、线粒体功能障碍和由该化合物诱导的生物能量紊乱。总的来说，这项研究的结果表明，干扰m6 A信号可能有助于AD的发病机制，可能是通过损害星形胶质细胞生物能量学。
The pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia, remains unclear. Over the past few years, evidence has accumulated indicating that perturbed cerebral bioenergetics and neuroinflammation may compromise cognitive functions and precedes the onset of AD and that impaired function of glial cells can likely contribute to the development of the disease. Recently, N6-methyladenosine (m6A) modification of RNA has been implicated in the regulation of different processes in the brain and to play a potential role in neurodegeneration. In the present study, we investigated the potential role of the m6A machinery enzymes in a streptozotocin (STZ) model of AD in human astrocytoma CCF-STTG1 cells. We observed that STZ-treated astrocytes expressed significantly higher levels of m6A demethylase fat mass and obesity-associated protein (FTO) and m6A reader YTHDF1 (YTH domain-containing family protein 1). Our experiments revealed that MO-I-500, a novel pharmacological inhibitor of FTO, can strongly reduce the adverse effects of STZ. Inhibition of FTO enhanced the survival of cells exposed to STZ and suppressed oxidative stress, apoptosis, elevated expression of glial fibrillary acidic protein, mitochondrial dysfunction, and bioenergetic disturbances induced by this compound. Overall, the results of this study indicate that perturbed m6A signaling may be contributing to AD pathogenesis, likely by compromising astrocyte bioenergetics.