• Kai-Fen Chuang, Chih-Hung Wang, Hang-Kang Chen, Yuan-Yung Lin, Chia-Hsin Lin, Yi-Chun Lin, Cheng-Ping Shih, Chao-Yin Kuo, Ying-Chuan Chen, and Hsin-Chien Chen.
• Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
• J Chin Med Assoc. 2023 Dec 1; 86 (12): 110111081101-1108.

BackgroundHearing loss is a global health issue and its etiopathologies involve complex molecular pathways. The ubiquitin-proteasome system has been reported to be associated with cochlear development and hearing loss. The gene related to anergy in lymphocytes ( GRAIL ), as an E3 ubiquitin ligase, has not, as yet, been examined in aging-related and noise-induced hearing loss mice models.MethodsThis 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.ResultsAt 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. RNA-seq 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.ConclusionThe 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.Copyright © 2023, the Chinese Medical Association.

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