Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss.

Adelaida M Celaya,Jose M Bermúdez-Muñoz,Rosario Perona,Silvia Murillo-Cuesta,Isabel Sánchez-Pérez,Isabel Varela-Nieto,Lourdes Rodríguez-de la Rosa,Laura Pintado-Berninches

doi:10.7554/elife.39159

Adelaida M Celaya, Jose M Bermúdez-Muñoz + Show 6 more

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https://doi.org/10.7554/elife.39159

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Abstract

Mitogen-activated protein kinases (MAPK) such as p38 and the c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. By contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that Dusp1 expression is age-regulated in the mouse cochlea. Dusp1 gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in Dusp1-/- mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration. Dusp1-/- mouse cochleae showed imbalanced redox status and dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.

Highlights

Hearing loss is the most common form of sensory impairment in humans, affecting over 7% of the world’s population (466 million people) according to WHO (WHO, 2018)
Our results show that: (i) DUSP1 is expressed in the mouse cochlea with a temporal age-regulated pattern; (ii) DUSP1 deficit leads to a premature onset of hearing loss and to an accelerated progression of the hearing-loss phenotype that is caused by the degeneration and death of the sensory epithelium and spiral ganglion neurons in the cochlea; and (iii) dysregulated oxidative balance and exacerbated inflammatory response are among the mechanisms underlying hearing loss in Dusp1-deficient mice
To confirm that the absence of DUSP1 increases the levels of reactive oxygen species (ROS), we studied the response of Mouse embryonic fibroblasts (MEFs) cells derived from Dusp1+/+ and Dusp1–/– mice to the oxidant stimulus H2O2

Summary

Introduction

Hearing loss is the most common form of sensory impairment in humans, affecting over 7% of the world’s population (466 million people) according to WHO (WHO, 2018) This impairing disability is caused by genetic defects, environmental factors or a combination of both. The phenotypic and genetic heterogeneity of hearing loss is still under study, and to this end animal studies and mice model systems are fundamental tools (Bowl et al, 2017). Their characterization will help us to develop new therapeutic strategies and to understand the molecular relationship between environmental and genetic factors in the establishment of the different types of sensorineural hearing loss

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