Downregulation of REST in the cochlea contributes to age-related hearing loss via the p53 apoptosis pathway

Abstract

Age-related hearing loss (AHL) is the most common sensory disorder amongst the elderly population. Although the degeneration of spiral ganglion neurons (SGNs) and hair cells (HCs) is considered to play a critical role in AHL, the mechanism has not been fully outlined. The repressor element 1-silencing transcription factor (REST) has recently been associated with mediating cell death in neurodegenerative diseases. However, whether REST induces degeneration of cochlear HCs and SGNs to contribute to AHL remains unknown. Here, we report that REST expression was decreased in HCs and SGNs in AHL mice. Conditional deletion of Rest in HCs and SGNs of 2-month-old mice resulted in hearing loss accompanied by the upregulation of p53, TNFR1(tumor necrosis factor receptor-1), and cleaved caspase-3. The p53 inhibitor pifithrin-α significantly attenuated SGN and HC damage and rescued hearing impairment in Rest cKO mice. Furthermore, downregulation of REST by H2O2 treatment induced apoptosis in the House Ear Institute Organ of Corti 1 cell, through the upregulation of p53. In contrast, overexpression of REST reversed the changes in p53 expression. In addition, REST was further shown to bind directly to the p53 promoter site, thereby inhibiting the effect of p53. Finally, in aged mice, the p53 inhibitor significantly reduced loss of HCs and SGNs, and subsequently improved hearing. In summary, our findings indicate that REST has a protective role in AHL, and that its deficiency upregulates p53 and induces cochlear cell apoptosis, which that leads to deafness.

Pathogenic REST variant causing Jones syndrome and a review of the literature

“…REST encodes a transcriptional regulator expressed in most non-neuronal cells and its expression is minimal in maturing hair cells and most neurons [ 7 ]. It contains a DNA- binding domain that can bind to a specific 21 base pair consensus sequence (RE-1) in the promoter region of its target genes to repress the transcription of the target genes [ 14 ]. REST acts as a master negative regulator of neurogenesis, a regulator of osteoblast differentiation, and a key repressor of gene expression in hypoxia [ 15 ].…”

“…REST expression was decreased in hair cells and spiral ganglion neurons in age-related hearing loss in mice. REST has a protective role in age-related hearing loss, and its deficiency upregulates p53 and induces cochlear cell apoptosis, which then leads to SNHL [ 14 ].…”

Pathogenic REST variant causing Jones syndrome and a review of the literature

“…REST is also involved in the organization of the auditory receptor cell stereocilium (14). Deletion of REST in the cochlea resulted in hearing impairment in mice and induced apoptosis of spiral ganglion neurons and hair cells (13), suggesting a loss-of-function disease mechanism. REST expression was decreased in hair cells and spiral ganglion neurons in age-related hearing loss in mice.…”

“…REST expression was decreased in hair cells and spiral ganglion neurons in age-related hearing loss in mice. REST has a protective role in age-related hearing loss, and its de ciency upregulates p53 and induces cochlear cell apoptosis, which then leads to deafness (13).…”

“…REST encodes a ubiquitously expressed transcriptional regulator (12). It contains a DNA-binding domain that can bind to a speci c 21 base pair consensus sequence (RE-1) in the promoter region of its target genes to repress the transcription of the target genes (13). REST acts as a master negative regulator of neurogenesis, a regulator of osteoblast differentiation, and a key repressor of gene expression in hypoxia (14).…”