Ingersoll Matthew A, Lutze Richard D, Kelmann Regina G, Kresock Daniel F, Marsh Jordan D, Quevedo Rene V, Zuo Jian, Teitz Tal
Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA.
Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA.
bioRxiv. 2023 Nov 13:2023.11.08.566316. doi: 10.1101/2023.11.08.566316.
Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, downregulated the MAPK kinase cascade and protected the KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, as excepted, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.
听力损失是日常生活中的一项主要残疾，保护听力的治疗干预措施将使世界上很大一部分人口受益。我们发现，与野生型KSR1同窝小鼠相比，组织中缺乏RAS 1蛋白激酶抑制因子（KSR1）的小鼠（种系敲除小鼠）对顺铂和噪声诱导的永久性听力损失具有抗性。KSR1在耳蜗中表达，是一种支架蛋白，它能使丝裂原活化蛋白激酶（MAPK）蛋白BRAF、MEK和ERK相互靠近，并通过耳蜗细胞中顺铂和噪声损伤诱导的磷酸化级联反应协助它们激活。删除KSR1蛋白可降低顺铂和噪声损伤后耳蜗细胞中的MAPK磷酸化级联反应，并在小鼠的三个测试频率中赋予高达30 dB SPL的听力保护。用FDA批准的口服BRAF抑制剂达拉非尼治疗可下调MAPK激酶级联反应，并保护KSR1野生型小鼠免受顺铂和噪声诱导的听力损失。正如预期的那样，达拉非尼治疗并未增强敲除KSR1小鼠的保护作用，这证明达拉非尼主要通过MAPK途径起作用。因此，在小鼠中消除KSR1基因表达或药物抑制MAPK细胞途径均可对顺铂和噪声诱导的听力损失产生显著保护作用。抑制MAPK途径，即一种对耳蜗细胞损伤作出反应的细胞途径，可能是保护和治疗听力损失的一种有价值的策略。
