Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland.
Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Life Sci Alliance. 2021 Nov 23;5(2). doi: 10.26508/lsa.202101068. Print 2022 Feb.
Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.
毛细胞静纤毛束和带状突触结构维持失败会导致听力损失。在这里，我们使用（脑源性神经营养因子）编码的 ER 稳态促进蛋白失活的小鼠模型研究了 ER 应激如何引发毛细胞病变。从听力开始，缺失导致外毛细胞静纤毛束排列紊乱，并降低整个音调轴的耳蜗声放大能力。在外毛细胞的高频区，病变最终导致静纤毛锥区的分子变化和强烈的静纤毛融合。在内毛细胞的高频区，缺失导致了带状突触退化。这种改变的表型强烈依赖于小鼠的遗传背景。总的来说，ER 稳态维持的失败导致了早期的静纤毛病和突触病，并加速了遗传原因引起的与年龄相关的听力损失的效应。相应地，人类患者的突变导致严重的感音神经性听力损失，从年轻时就开始。因此，我们提出 MANF 作为一种新的蛋白质和 ER 应激作为一种机制，调节小鼠和人类听觉毛细胞的维持。
