Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Departments of Surgery and Neuroscience, University of California San Diego and Veterans Administration Medical Center, La Jolla, CA 92093, USA; Translational Neuroscience Facility, Department of Physiology, NSW Australia, Sydney, NSW 2052, Australia.
Cell Rep. 2020 Nov 24;33(8):108431. doi: 10.1016/j.celrep.2020.108431.
Exposure to excessive sound causes noise-induced hearing loss through complex mechanisms and represents a common and unmet neurological condition. We investigate how noise insults affect the cochlea with proteomics and functional assays. Quantitative proteomics reveals that exposure to loud noise causes proteotoxicity. We identify and confirm hundreds of proteins that accumulate, including cytoskeletal proteins, and several nodes of the proteostasis network. Transcriptomic analysis reveals that a subset of the genes encoding these proteins also increases acutely after noise exposure, including numerous proteasome subunits. Global cochlear protein ubiquitylation levels build up after exposure to excess noise, and we map numerous posttranslationally modified lysines residues. Several collagen proteins decrease in abundance, and Col9a1 specifically localizes to pillar cell heads. After two weeks of recovery, the cochlea selectively elevates the abundance of the protein synthesis machinery. We report that overstimulation of the auditory system drives a robust cochlear proteotoxic stress response.
暴露于过量的声音会通过复杂的机制引起噪声性听力损失，这是一种常见且未得到满足的神经学状况。我们通过蛋白质组学和功能测定来研究噪声损伤如何影响耳蜗。定量蛋白质组学显示，暴露于强噪声会引起蛋白毒性。我们鉴定并确认了数百种积累的蛋白质，包括细胞骨架蛋白和几个蛋白质稳态网络的节点。转录组分析显示，编码这些蛋白质的一部分基因在噪声暴露后也会急性增加，包括许多蛋白酶体亚基。暴露于过量噪声后，整个耳蜗的蛋白质泛素化水平会升高，我们还绘制了许多翻译后修饰的赖氨酸残基。几种胶原蛋白的丰度降低，Col9a1 特异性定位于支柱细胞头部。两周恢复后，耳蜗选择性地增加蛋白质合成机制的丰度。我们报告说，听觉系统的过度刺激会引发强烈的耳蜗蛋白毒性应激反应。
