ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23(erl/erl) mutant mice.
ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23(erl/erl) mutant mice.
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ER 应激抑制剂可减轻 Cdh23(erl/erl) 突变小鼠的听力损失和毛细胞死亡
DOI：
10.1038/cddis.2016.386
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发表时间：
2016-11-24
影响因子：
9
通讯作者：
Zheng QY
中科院分区：
文献类型：
--
作者：
Hu J;Li B;Apisa L;Yu H;Entenman S;Xu M;Stepanyan R;Guan BJ;Müller U;Hatzoglou M;Zheng QY
听力损失是人类最常见的感觉障碍之一。小鼠突变体模型帮助我们更好地理解听力损失的机制。最近，我们发现钙黏蛋白23（Cdh23）基因的耳隆（erl）突变会因毛细胞凋亡导致听力损失。在这项研究中，我们旨在揭示毛细胞中凋亡上游的分子通路，以开发比抗凋亡策略更有效的治疗方法。我们的研究结果表明，内质网（ER）应激是导致erl小鼠毛细胞凋亡和听力损失的最早分子事件。我们还报告称，内质网应激抑制剂沙芦布林（Sal）能够延缓听力损失的进展并保护毛细胞。我们的研究结果提供了证据，表明针对内质网应激发展过程中的信号通路进行治疗，可在早期预防毛细胞凋亡，并且比针对下游因素（如静纤毛连接退化和凋亡）的治疗能取得更好的效果。
Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reticulum (ER) stress is the earliest molecular event leading to the apoptosis of hair cells and hearing loss in erl mice. We also report that the ER stress inhibitor, Salubrinal (Sal), could delay the progression of hearing loss and preserve hair cells. Our results provide evidence that therapies targeting signaling pathways in ER stress development prevent hair cell apoptosis at an early stage and lead to better outcomes than those targeting downstream factors, such as tip-link degeneration and apoptosis.