GRAIL gene knockout mice protect against aging-related and noise-induced hearing loss

Sep 29, 2026

Uploaded by Ophelia

Hearing loss poses a major global health challenge with complex molecular causes. This study focuses on the gene related to anergy in lymphocytes (GRAIL), an E3 ubiquitin ligase, and evaluates its role in aging-related and noise-induced hearing loss using wild-type and GRAIL knockout mice. Cochlear hair cells and synaptic ribbons were assessed by immunofluorescence, hearing by auditory brainstem response, and molecular targets by RNA-sequencing. Results show GRAIL deficiency reduces threshold elevation, hair cell loss, synaptic ribbon loss, and noise-driven gene expression changes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

INTRODUCTION

Hearing loss overview and common etiologies

Molecular hypotheses of sensorineural hearing loss

METHODS

Animal models and experimental design

Immunofluorescence and auditory brainstem response

RNA-sequencing for gene expression comparisons

RESULTS

Outcomes at 12-month follow-up

Outcomes after noise exposure across time points

Differential gene expression after noise exposure

CONCLUSION

Protective effect of GRAIL deficiency and proposed mechanisms

J Chin MedAssoc Original article GRAIL gene knockout mice protect against agingrelated and noise-induced hearing loss Kai-Fen Chuanga, Chih-Hung Wanga,b,c, Hang-Kang Chena, Yuan-Yung Lina,b, Chia-Hsin Lina, Yi-Chun Lina, Cheng-Ping Shiha, Chao-Yin Kuoa, Ying-Chuan Chend,* , Hsin-Chien Chena,* aDepartment of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC; bGraduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; cDivision of Otolaryngology, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, Taiwan; dDepartment of Physiology & Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC Abstract Background: Hearing loss is a global health issue and its etiopathologies involve complex molecular pathways. The ubiquitinproteasome system has been reported to be associated with cochlear development and hearing loss. The gene related to anergyin lymphocytes (GRAIL), as an E3 ubiquitin ligase, has not, as yet, been examined in aging-related and noise-induced hearing loss mice models. Methods: This study used wild-type (WT) and GRAIL knockout (KO) mice to examine cochlear hair cells and synaptic ribbons using immunofluorescence staining. The hearing in WT and KO mice was detected using auditory brainstem response. Gene expression patterns were compared using RNA-sequencing to identify potential targets during the pathogenesis of noise-induced hearing loss in WT and KO mice. Results: At the 12-month follow-up, GRAIL KO mice had significantly less elevation in threshold level and immunofluorescence staining showed less loss of outer hair cells and synaptic ribbons in the hook region compared with GRAIL WT mice. At days 1, 14, and 28 after noise exposure, GRAIL KO mice had significantly less elevation in threshold level than WT mice. After noise exposure, GRAIL KO mice showed less loss of outer hair cells in the cochlear hook and basal regions compared with WT mice. Moreover, immunofluorescence staining showed less loss of synaptic ribbons in the hook regions of GRAIL KO mice than of WT mice. RNAseq analysis results showed significant differences in C-C motif chemokine ligand 19 (CCL19), C-C motif chemokine ligand 21 (CCL21), interleukin 25 (IL25), glutathione peroxidase 6 (GPX6), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1) genes after noise exposure. Conclusion: The present data demonstrated that GRAIL deficiency protects against aging-related and noise-induced hearing loss. The mechanism involved needs to be further clarified from the potential association with synaptic modulation, inflammation, and oxidative stress. Keywords: Aging; Cochlea; GRAIL; Hearing loss; Noise; RNF128; Ubiquitin-proteasome system 1. INTRODUCTION Hearing loss affects over 20% of the world’s population. The annual additional investment attributed to hearing care amounted to US$ 750 billion, especially in low- and middleincome countries.1 The term sensorineural hearing loss (SNHL) refers to problems that involve transmission at and after the * Address correspondence. Dr. Ying-Chuan Chen, Department of Physiology & Biophysics, National Defense Medical Center, Tri-Service General Hospital, 161, Section 6, Ming-Chun East Road, Taipei 114, Taiwan, ROC. E-mail address: [addy0918@gmail.com](addy0918@gmail.com) (Y.-C. Chen); Dr. Hsin-Chien Chen, Department of Otolaryngology-Head and Neck Surgery, Tri-service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Kung Road, Taipei 114, Taiwan, [ROC. E-mail address: acolufreia@yahoo.com.tw](ROC. E-mail address: acolufreia@yahoo.com.tw) (H.-C. Chen). Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article. Journal of Chinese Medical Association. (2023) 86: 1101-1108. Received May 11, 2023; accepted September 9, 2023. doi: 10. 1097/J

FAQs

What is the main purpose of the study on GRAIL knockout mice?

To determine whether GRAIL deficiency protects against aging-related and noise-induced hearing loss and to identify associated molecular changes.

How were hearing function and cochlear cellular changes evaluated?

Hearing was measured using auditory brainstem response, while cochlear hair cells and synaptic ribbons were assessed via immunofluorescence staining.

What key findings were observed in GRAIL knockout mice after noise exposure?

GRAIL knockout mice showed significantly less elevation in hearing threshold and less loss of outer hair cells and synaptic ribbons compared with wild-type mice.

Sep 29, 2026

Uploaded by Ophelia