2. Academic Validation
  3. Downregulation of REST in the cochlea contributes to age-related hearing loss via the p53 apoptosis pathway

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

  • Cell Death Dis. 2022 Apr 13;13(4):343. doi: 10.1038/s41419-022-04774-0.
Hongchen Li  # 1 2 3,  Mingshun Lu  # 1 2 3,  Haiwei Zhang 1 2 3,  Shengnan Wang 1 2 3,  Fei Wang 1 2 3,  Xueya Ma 1 2 3,  Jiaxi Liu 1 2 3,  Xinyu Li 1 2 3,  Haichao Yang 1 2 3,  Haitao Shen 4,  Ping Lv 5 6 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
  • 2 Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
  • 3 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
  • 4 Lab of Pathology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. haitaoshen78@hotmail.com.
  • 5 Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. lping77@hotmail.com.
  • 6 Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. lping77@hotmail.com.
  • 7 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, 050017, China. lping77@hotmail.com.
  • # Contributed equally.
PMID: 35418568 DOI: 10.1038/s41419-022-04774-0
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.

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