title: Impaired unfolded protein response in the degeneration of cochlea cells in a mouse model of age-related hearing loss.
abstract: Endoplasmic reticulum (ER) stress triggers the unfolded protein response (UPR) to prevent the accumulation of proteins in an aberrant conformation. The UPR can restore homeostasis by upregulating ER chaperones, such as glucose-regulated protein 78kD (GRP78), to refold the incorrectly handled protein, and by degrading the misfolded proteins via the ubiquitin-proteasome and autophagy-lysosome system. ER stress was recently demonstrated to be involved in the pathogenesis of age-related diseases. In this study, we measured the expression levels of GRP78 and ubiquitinated proteins in the cochleae of young C57BL/6 mice and aged mice to assess the capacity of the UPR. The lower expression of GRP78 and the increased number of ubiquitinated proteins observed in the cochleae of aged mice suggested that the capacity of the UPR was impaired and that the cell death pathway was activated. We found a markedly increased expression of the ER-related pro-apoptotic factor C/EBP homologous protein (CHOP) in the cochleae of aged mice, whereas the level of cleaved caspase-12 did not differ between the two groups. In addition, the cleavage of caspase-9, caspase-3 and poly [ADP-ribose] polymerase 1 was significantly increased in the aged cochleae, suggesting the activation of apoptosis in the cochleae resulting from the cross-talk between the ER and mitochondria through CHOP. These results indicated that impaired UPR in the cochleae of aged C57BL/6 mice resulting in ER stress may lead to apoptosis that is dependent on the mitochondrial pathway and that ER stress induced apoptosis may not be mediated by caspase-12.
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China. Electronic address: wenly-kong@163.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China; Institute of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China. Electronic address: entwjkong@hust.edu.cn.
authors.forename: Weijia
authors.initials: W
authors.lastname: Kong
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053454:Caspase 12 / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology; D003051:Cochlea / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D034381:Hearing Loss / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D012684:Sensory Thresholds / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C506440:Casp12 protein, mouse; C505409:Casp3 protein, mouse; D053454:Caspase 12; D053148:Caspase 3
keywords: Age-related hearing loss; C/EBP homologous protein; Caspase-12; Endoplasmic reticulum stress; Glucose-regulated protein 78kD; Unfolded protein response