Abstract
Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl), revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.
Highlights
Hearing loss and vestibular dysfunction are among the most common disorders requiring medical attention
We have developed methods to systematically identify modulatory pathways altering hair cell response to aminoglycoside antibiotic exposure by taking advantage of in vivo labeling of lateral line hair cells with vital dyes
We reasoned that by examining animals treated with concentrations of neomycin at low or high ends of the dose-response curve, we should be able to identify modifiers that alter susceptibility to neomycin-induced hair cell death (Figure 1C)
Summary
Hearing loss and vestibular dysfunction are among the most common disorders requiring medical attention. Over a third of older adults suffer from these conditions. Studies of both laboratory animals and humans reveal tremendous variation in hearing loss due to ageing as well as exogenous challenges such as ototoxic drugs and noise exposure, and show that this variability can be at least partially understood using genetic methods [1,2,3,4,5]. Rapid progress has been made using genetics to understand the molecular basis for congenital deafness [6], but adult-onset hearing loss is poorly understood despite its overwhelming prevalence. Understanding how hair cell death is genetically modified by intrinsic and extrinsic challenges should lead to identification of new therapeutic targets for prevention of inner ear damage
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