Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.
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DOI：
10.1016/j.redox.2018.08.002
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Mammano F
中科院分区：
文献类型：
--
作者：
Fetoni AR;Zorzi V;Paciello F;Ziraldo G;Peres C;Raspa M;Scavizzi F;Salvatore AM;Crispino G;Tognola G;Gentile G;Spampinato AG;Cuccaro D;Guarnaccia M;Morello G;Van Camp G;Fransen E;Brumat M;Girotto G;Paludetti G;Gasparini P;Cavallaro S;Mammano F
GJB2（编码连接蛋白 26 (Cx26) 的基因）的突变是感音神经性听力障碍的最常见原因。截短变体 35delG 决定了 Cx26 蛋白功能的完全丧失，是多个人群中普遍存在的 GJB2 突变。在这里，我们生成并分析了 Gjb2+/- 小鼠作为 35delG 杂合人类携带者的模型。与对照小鼠相比，Gjb2+/- 小鼠的听觉脑干反应（ABR）和畸变产物耳声发射（DPOAE）随着时间的推移恶化得更快，表明它们受到加速年龄相关性听力损失（ARHL）或老年性耳聋的影响。我们将 Gjb2+/- 小鼠的听觉表型与耳蜗管细胞凋亡和氧化损伤、连接蛋白半通道释放谷胱甘肽减少、通过耳蜗间隙连接向感觉上皮输送营养减少以及受核因子红细胞 2 相关因子 2 转录控制的基因表达失调联系起来。 (Nrf2)，氧化还原应激耐受性的关键调节因子。此外，在来自欧洲、高加索和中亚的 4091 名具有听力表型的个体（包括 1076 名老年性耳聋患者和 1290 名健康匹配对照）的大型队列中，检测到与 Nrf2 通路相关的两个基因（PRKCE 和 TGFB1）存在统计学上显着的全基因组关联（p 值 < 4× 10−2）。我们的结论是：（i）Nrf2 通路的元件对于维持听力至关重要，（ii）它们的功能障碍可能在人类老年性耳聋的发病机制中发挥重要作用。 Cx26 部分缺失会加速 Gjb2+/- 小鼠听力损伤的进展。由于氧化还原失衡，听觉器官受到细胞凋亡增加的影响。 Nrf2/ARE 途径控制的几个基因的表达失调。全基因组关联在老年性耳聋患者中检测到其中两个基因。这项工作为老年性耳聋的发病机制及其预防提供了新的线索。
Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis. Partial loss of Cx26 accelerates hearing impairment progression in Gjb2+/- mice. The auditory organ is affected by increased apoptosis due to redox imbalance. The expression of several genes controlled by the Nrf2/ARE pathway is deregulated. Genome-wide association detected two of these genes in humans with presbycusis. This work sheds new light on the etiopathogenesis of presbycusis and its prevention.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.4
作者：
Chen, Po-Han;Smith, Timothy J.;Chi, Jen-Tsan
通讯作者：
Chi, Jen-Tsan
影响因子：
11.4
作者：
Chi, Yuan;Zhang, Xiling;Zhang, Zhen;Mitsui, Takahiko;Kamiyama, Manabu;Takeda, Masayuki;Yao, Jian
通讯作者：
Yao, Jian
影响因子：
3.7
作者：
Chang Q;Tang W;Ahmad S;Zhou B;Lin X
通讯作者：
Lin X
影响因子：
3.8
作者：
Aoki, Y;Sato, H;Yamamoto, M
通讯作者：
Yamamoto, M