title: ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erlmutant mice.
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.
authors.affiliation: Transformative Otology and Neuroscience Center, Binzhou Medical University, Yantai, Shandong, China.|Department of Otorhinolaryngology-HNS, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.|Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Hu
authors.affiliation: Transformative Otology and Neuroscience Center, Binzhou Medical University, Yantai, Shandong, China.|Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Apisa
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Heping
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Shami
authors.initials: S
authors.lastname: Entenman
authors.affiliation: Department of Otorhinolaryngology-HNS, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.|Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Stepanyan
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.affiliation: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Qing Yin
authors.initials: QY
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002934:Cinnamates / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034381:Hearing Loss / Q000473:pathology*; D006360:Heat-Shock Proteins; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015820:Cadherins; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D013890:Thiourea; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C499091:Cdh23 protein, mouse; C496827:salubrinal