PRDX1 activates autophagy via the PTEN-AKT signaling pathway to protect against cisplatin-induced spiral ganglion neuron damage.
PRDX1 activates autophagy via the PTEN-AKT signaling pathway to protect against cisplatin-induced spiral ganglion neuron damage.
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PRDX 1通过PTEN-AKT信号通路激活自噬以保护免受顺铂诱导的螺旋神经节神经元损伤。
DOI：
10.1080/15548627.2021.1905466
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发表时间：
2021-12
期刊：
影响因子：
13.3
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Liu W;Xu L;Wang X;Zhang D;Sun G;Wang M;Wang M;Han Y;Chai R;Wang H
螺旋神经节神经元 (SGN) 是将声音信号从内耳传递到脑干的听觉神经元。耳毒性药物顺铂会损伤SGN，从而导致感音神经性听力损失（SNHL），目前尚无预防或治疗方法。巨自噬/自噬在 SGN 发生过程中发挥着关键作用，但自噬对顺铂诱导的 SGN 损伤的影响尚不清楚。在这里，我们首先发现顺铂损伤后 SGN 中的自噬流被激活。与自噬激活剂雷帕霉素共同治疗后，顺铂诱导的SGN凋亡和相关听力损失得到缓解，而自噬抑制剂3-甲基腺嘌呤则加剧了这些情况，表明自噬在体外和体内均在顺铂处理的SGN中发挥了神经保护作用，而不是诱导SGN死亡。我们进一步证明，自噬减弱了活性氧（ROS）的积累，减轻了顺铂诱导的 SGN 氧化应激，从而介导其保护作用。值得注意的是，抗氧化酶 PRDX1（过氧化还原蛋白 1）在调节 SGN 中自噬中的作用首次被确定。 PRDX1缺乏会抑制顺铂暴露后的自噬并增加SGN损失，而通过药理学或腺相关病毒激活自噬上调PRDX1，从而抑制ROS积累和细胞凋亡，并减弱顺铂引起的SGN损失。最后，我们表明 PRDX1 触发 SGN 中自噬的潜在机制至少部分是通过激活 PTEN-AKT 信号通路。这些发现表明通过自噬激活改善药物诱导的 SNHL 的潜在治疗靶点。缩写：3-MA：3-甲基腺嘌呤； AAV：腺相关病毒； ABR：听觉脑干反应； AKT/蛋白激酶B：胸腺瘤病毒原癌基因； Baf：巴弗洛霉素A1； CAP：复合动作电位； COX4I1：细胞色素c氧化酶亚基4I1； Cys：半胱氨酸； ER：内质网； H2O2：过氧化氢； HC：毛细胞； MAP1LC3B/LC3B：微管相关蛋白1轻链3β； NAC：N-乙酰半胱氨酸； PRDX1：过氧化还原蛋白1； PTEN：磷酸酶和张力蛋白同系物； RAP：雷帕霉素； ROS：活性氧； SGN：螺旋神经节神经元； SNHL：感音神经性听力损失； SQSTM1/p62: 隔离体 1; TOMM20：线粒体外膜转位酶20； TUNEL：末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记； WT：野生型。
Spiral ganglion neurons (SGNs) are auditory neurons that relay sound signals from the inner ear to the brainstem. The ototoxic drug cisplatin can damage SGNs and thus lead to sensorineural hearing loss (SNHL), and there are currently no methods for preventing or treating this. Macroautophagy/autophagy plays a critical role in SGN development, but the effect of autophagy on cisplatin-induced SGN injury is unclear. Here, we first found that autophagic flux was activated in SGNs after cisplatin damage. The SGN apoptosis and related hearing loss induced by cisplatin were alleviated after co-treatment with the autophagy activator rapamycin, whereas these were exacerbated by the autophagy inhibitor 3-methyladenine, indicating that instead of inducing SGN death, autophagy played a neuroprotective role in SGNs treated with cisplatin both in vitro and in vivo. We further demonstrated that autophagy attenuated reactive oxygen species (ROS) accumulation and alleviated cisplatin-induced oxidative stress in SGNs to mediate its protective effects. Notably, the role of the antioxidant enzyme PRDX1 (peroxiredoxin 1) in modulating autophagy in SGNs was first identified. Deficiency in PRDX1 suppressed autophagy and increased SGN loss after cisplatin exposure, while upregulating PRDX1 pharmacologically or by adeno-associated virus activated autophagy and thus inhibited ROS accumulation and apoptosis and attenuated SGN loss induced by cisplatin. Finally, we showed that the underlying mechanism through which PRDX1 triggers autophagy in SGNs was, at least partially, through activation of the PTEN-AKT signaling pathway. These findings suggest potential therapeutic targets for the amelioration of drug-induced SNHL through autophagy activation. Abbreviations: 3-MA: 3-methyladenine; AAV : adeno-associated virus; ABR: auditory brainstem responses; AKT/protein kinase B: thymoma viral proto-oncogene; Baf: bafilomycin A1; CAP: compound action potential; COX4I1: cytochrome c oxidase subunit 4I1; Cys: cysteine; ER: endoplasmic reticulum; H2O2: hydrogen peroxide; HC: hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NAC: N-acetylcysteine; PRDX1: peroxiredoxin 1; PTEN: phosphatase and tensin homolog; RAP: rapamycin; ROS: reactive oxygen species; SGNs: spiral ganglion neurons; SNHL: sensorineural hearing loss; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling; WT: wild type.
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DOI：
10.1016/j.bbrc.2014.04.123
发表时间：
2014-06-13
影响因子：
3.1
作者：
Fang, Bin;Xiao, Hongjun
通讯作者：
Xiao, Hongjun
影响因子：
4.2
作者：
Cho, Kyung-Hwa;Park, Ji-Hye;Yang, Sei-Hoon
通讯作者：
Yang, Sei-Hoon
影响因子：
1.7
作者：
Dong, Youyi;Sui, Li;Tokuda, Masaaki
通讯作者：
Tokuda, Masaaki
影响因子：
3.4
作者：
Chen, Jianhua;Zhang, Lemeng;Yi, Huihuang
通讯作者：
Yi, Huihuang
DOI：
10.1126/science.1241062
发表时间：
2014-05-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Géléoc GS;Holt JR
通讯作者：
Holt JR