Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux
ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann–Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and differen...
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.742714/full |
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| author | Shiwei Qiu Shiwei Qiu Weihao Zhao Weihao Zhao Xue Gao Dapeng Li Weiqian Wang Bo Gao Weiju Han Shiming Yang Pu Dai Peng Cao Yongyi Yuan |
| author_facet | Shiwei Qiu Shiwei Qiu Weihao Zhao Weihao Zhao Xue Gao Dapeng Li Weiqian Wang Bo Gao Weiju Han Shiming Yang Pu Dai Peng Cao Yongyi Yuan |
| author_sort | Shiwei Qiu |
| collection | DOAJ |
| description | ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann–Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanisms remain unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in Atp6v1b2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment. |
| first_indexed | 2024-12-22T11:44:43Z |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T11:44:43Z |
| publishDate | 2021-10-01 |
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| spelling | doaj.art-877b69ea059643d79e213216d463f39f2022-12-21T18:27:10ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-10-01910.3389/fcell.2021.742714742714Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton FluxShiwei Qiu0Shiwei Qiu1Weihao Zhao2Weihao Zhao3Xue Gao4Dapeng Li5Weiqian Wang6Bo Gao7Weiju Han8Shiming Yang9Pu Dai10Peng Cao11Yongyi Yuan12Department of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaThe Institute of Audiology and Balance Science, Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaDepartment of Otolaryngology General Hospital of Tibet Military Region, Lhasa, ChinaDepartment of Otolaryngology, PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaNational Institute of Biological Sciences, Beijing, ChinaDepartment of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Genetic Testing Center for Deafness, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; Key Lab of Hearing Impairment Science of Ministry of Education; Key Lab of Hearing Impairment Prevention and Treatment of Beijing, Beijing, ChinaATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann–Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanisms remain unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in Atp6v1b2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.https://www.frontiersin.org/articles/10.3389/fcell.2021.742714/fullsyndromic hearing lossAtp6v1b2lysosomeapoptosisfunction compensation |
| spellingShingle | Shiwei Qiu Shiwei Qiu Weihao Zhao Weihao Zhao Xue Gao Dapeng Li Weiqian Wang Bo Gao Weiju Han Shiming Yang Pu Dai Peng Cao Yongyi Yuan Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux Frontiers in Cell and Developmental Biology syndromic hearing loss Atp6v1b2 lysosome apoptosis function compensation |
| title | Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux |
| title_full | Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux |
| title_fullStr | Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux |
| title_full_unstemmed | Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux |
| title_short | Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux |
| title_sort | syndromic deafness gene atp6v1b2 controls degeneration of spiral ganglion neurons through modulating proton flux |
| topic | syndromic hearing loss Atp6v1b2 lysosome apoptosis function compensation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.742714/full |
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