ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erl mutant mice.

Juan Hu,Heping Yu,Maria Hatzoglou,Shami Entenman,Ulrich Müller,Luke Apisa,Qing Yin Zheng,Bo-Jhih Guan,Ruben Stepanyan,Bo Li,Min Xu

doi:10.1038/cddis.2016.386

Abstract

Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reticulum (ER) stress is the earliest molecular event leading to the apoptosis of hair cells and hearing loss in erl mice. We also report that the ER stress inhibitor, Salubrinal (Sal), could delay the progression of hearing loss and preserve hair cells. Our results provide evidence that therapies targeting signaling pathways in ER stress development prevent hair cell apoptosis at an early stage and lead to better outcomes than those targeting downstream factors, such as tip-link degeneration and apoptosis.

Highlights

In humans, Cdh[23] mutations cause nonsyndromic autosomal recessive deafness (DFNB12) and Usher syndrome type 1D, USH1D, characterized by deafness associated with retinitis pigmentosa and vestibular dysfunction.[4,5,6] In mice, Cdh[23] mutations lead to hearing loss with or without vestibular dysfunction.[7,8,9] Recently, we identified a novel point mutation (T208C) of Cdh[23] and named this mutation erlong.[10]
CDH23 partly failed to reach the top of hair bundles and were co-localized with binding protein (BiP) in the subapical regions of outer hair cells (OHCs) in erl mice
No detectable CDH23 signal was found in B6 mice, while in erl mice, many spots of CDH23 signal was detected in this region (n = 3 mice per group)

Summary

Introduction

Cdh[23] mutations cause nonsyndromic autosomal recessive deafness (DFNB12) and Usher syndrome type 1D, USH1D, characterized by deafness associated with retinitis pigmentosa and vestibular dysfunction.[4,5,6] In mice, Cdh[23] mutations lead to hearing loss with or without vestibular dysfunction.[7,8,9] Recently, we identified a novel point mutation (T208C) of Cdh[23] and named this mutation erlong (erl).[10]. Blocking ER stress pro-apoptosis factors could reduce cell death in zebrafish mutants.[15] Because the erl mutation affects Cdh[23], the same gene that causes USH1D in humans, it is reasonable to speculate that the ERL-CDH23 protein might endure defective trafficking, triggering ER stress and leading to hair cell apoptosis and hearing impairment in erl mutants. We report here that the small molecular compound of ER stress inhibitor Salubrinal (Sal) could slow down the progression of hearing loss and hair cell death in erl mice. These results offer a potential therapy for human DFNB12 and possibly protect the visual function of individuals with Usher syndrome

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