DNAJC14 Ameliorates Inner Ear Degeneration in the DFNB4 Mouse Model
| Autor: | Jae Young Choi, Byunghwa Noh, Seong Kug Eo, Hye Ji Choi, Sushil Devkota, Hyunjae Lee, Min Goo Lee, Jin Young Choi, Han Woong Lee, Ik Hyun Jeon, Jinsei Jung |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse pendrin lcsh:QH426-470 Hearing loss Pendred syndrome H723R KCNJ10 Article 03 medical and health sciences 0302 clinical medicine flavivirus unconventional secretion Genetics medicine otorhinolaryngologic diseases DFNB4 chaperone Inner ear Endolymphatic hydrops lcsh:QH573-671 Molecular Biology DNAJC14 biology lcsh:Cytology genetic hearing loss Pendrin slc26a4 medicine.disease Cell biology lcsh:Genetics 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Spiral ligament biology.protein Molecular Medicine sense organs medicine.symptom |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 188-197 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | The His723Arg (H723R) mutation in SLC26A4, encoding pendrin, is the most prevalent mutation in East Asia, resulting in DFNB4, an autosomal recessive type of genetic hearing loss. Although the main pathological mechanism of H723R was identified as a protein-folding defect in pendrin, there is still no curative treatment for associated hearing loss. Here, we show that H723R-pendrin expression and activity are rescued by activation of the chaperonin DNAJC14. In vitro, DNAJC14 was activated via Japanese encephalitis virus (JEV) inoculation, and toxin-attenuated JEV rescued the surface expression and anion exchange activity of H723R-pendrin. Human H723R-pendrin transgenic mice (hH723R Tg) were established in a mouse slc26a4 knockout background, in which only hH723R-pendrin was expressed in the inner ear (Pax2-Cre dependent) to mimic human DFNB4 pathology. Crossing hH723R Tg with DNAJC14-overexpressing mice resulted in reduced cochlear hydrops and more preserved outer hair cells in the cochlea compared to those in hH723R Tg mice. Furthermore, the stria vascularis and spiral ligament were thicker and KCNJ10 expression was increased with DNAJC14 overexpression; however, hearing function and enlarged endolymphatic hydrops were not recovered. These results indicate that DNAJC14 overexpression ameliorates the cochlear degeneration caused by misfolded pendrin and might be a potential therapeutic target for DFNB4. |
| Databáze: | OpenAIRE |
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