Impaired unfolded protein response in the degeneration of cochlea cells in a mouse model of age-related hearing loss.
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.
['Wang|Wenwen|W|', 'Sun|Yu|Y|', 'Chen|Sen|S|', 'Zhou|Xingxing|X|', 'Wu|Xia|X|', 'Kong|Wen|W|', 'Kong|Weijia|W|']
D000375:Aging D000818:Animals D017209:Apoptosis D053454:Caspase 12 D053148:Caspase 3 D003051:Cochlea D004195:Disease Models, Animal D000091342:Endoplasmic Reticulum Chaperone BiP D059865:Endoplasmic Reticulum Stress D016057:Evoked Potentials, Auditory, Brain Stem D034381:Hearing Loss D006360:Heat-Shock Proteins D008810:Mice, Inbred C57BL D012684:Sensory Thresholds D056811:Unfolded Protein Response
Unfolded protein response Age-related hearing loss Glucose-regulated protein 78kD C/EBP homologous protein Caspase-12 Endoplasmic reticulum stress