Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway
Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718305445 |
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doaj-4157f176ca6c433d98c82de45af9277e |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Anna Rita Fetoni Veronica Zorzi Fabiola Paciello Gaia Ziraldo Chiara Peres Marcello Raspa Ferdinando Scavizzi Anna Maria Salvatore Giulia Crispino Gabriella Tognola Giulia Gentile Antonio Gianmaria Spampinato Denis Cuccaro Maria Guarnaccia Giovanna Morello Guy Van Camp Erik Fransen Marco Brumat Giorgia Girotto Gaetano Paludetti Paolo Gasparini Sebastiano Cavallaro Fabio Mammano |
| spellingShingle |
Anna Rita Fetoni Veronica Zorzi Fabiola Paciello Gaia Ziraldo Chiara Peres Marcello Raspa Ferdinando Scavizzi Anna Maria Salvatore Giulia Crispino Gabriella Tognola Giulia Gentile Antonio Gianmaria Spampinato Denis Cuccaro Maria Guarnaccia Giovanna Morello Guy Van Camp Erik Fransen Marco Brumat Giorgia Girotto Gaetano Paludetti Paolo Gasparini Sebastiano Cavallaro Fabio Mammano Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway Redox Biology |
| author_facet |
Anna Rita Fetoni Veronica Zorzi Fabiola Paciello Gaia Ziraldo Chiara Peres Marcello Raspa Ferdinando Scavizzi Anna Maria Salvatore Giulia Crispino Gabriella Tognola Giulia Gentile Antonio Gianmaria Spampinato Denis Cuccaro Maria Guarnaccia Giovanna Morello Guy Van Camp Erik Fransen Marco Brumat Giorgia Girotto Gaetano Paludetti Paolo Gasparini Sebastiano Cavallaro Fabio Mammano |
| author_sort |
Anna Rita Fetoni |
| title |
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway |
| title_short |
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway |
| title_full |
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway |
| title_fullStr |
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway |
| title_full_unstemmed |
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway |
| title_sort |
cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of nfr2 pathway |
| publisher |
Elsevier |
| series |
Redox Biology |
| issn |
2213-2317 |
| publishDate |
2018-10-01 |
| description |
Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis. Keywords: Age-related hearing loss, Connexin 26, Mouse models, Genome-wide association study, Hair cells, Spiral ganglion neurons |
| url |
http://www.sciencedirect.com/science/article/pii/S2213231718305445 |
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doaj-4157f176ca6c433d98c82de45af9277e2020-11-25T01:56:45ZengElsevierRedox Biology2213-23172018-10-0119301317Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathwayAnna Rita Fetoni0Veronica Zorzi1Fabiola Paciello2Gaia Ziraldo3Chiara Peres4Marcello Raspa5Ferdinando Scavizzi6Anna Maria Salvatore7Giulia Crispino8Gabriella Tognola9Giulia Gentile10Antonio Gianmaria Spampinato11Denis Cuccaro12Maria Guarnaccia13Giovanna Morello14Guy Van Camp15Erik Fransen16Marco Brumat17Giorgia Girotto18Gaetano Paludetti19Paolo Gasparini20Sebastiano Cavallaro21Fabio Mammano22CNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy; Institute of Otolaryngology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168 Rome, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, ItalyCNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, ItalyCNR Institute of Electronics, Computer and Telecommunication Engineering, 20133 Milano, ItalyCNR Institute of Neurological Sciences, 95126 Catania, ItalyCNR Institute of Neurological Sciences, 95126 Catania, ItalyCNR Institute of Neurological Sciences, 95126 Catania, ItalyCNR Institute of Neurological Sciences, 95126 Catania, ItalyCNR Institute of Neurological Sciences, 95126 Catania, ItalyCenter of Medical Genetics, University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610 Antwerp, BelgiumDepartment of Biomedical Sciences, University of Antwerp, 2650 Antwerp, BelgiumDept Med Surg & Hlth Sci, University of Trieste, Trieste, Italy; IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, ItalyDept Med Surg & Hlth Sci, University of Trieste, Trieste, Italy; IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, ItalyUniversità Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy; Institute of Otolaryngology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168 Rome, ItalyDept Med Surg & Hlth Sci, University of Trieste, Trieste, Italy; IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy; Corresponding author at: Dept Med Surg & Hlth Sci, University of Trieste, Trieste, Italy.CNR Institute of Neurological Sciences, 95126 Catania, Italy; Corresponding author at: CNR Institute of Neurological Sciences, Via P. Gaifami 18, 95126 Catania, Italy.CNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; University of Padova, Department of Physics and Astronomy “G. Galilei”, Padova, Italy; Corresponding author at: CNR Institute of Cell Biology and Neurobiology, Via E. Ramarini 32, 00015 Monterotondo, RM, Italy.Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis. Keywords: Age-related hearing loss, Connexin 26, Mouse models, Genome-wide association study, Hair cells, Spiral ganglion neuronshttp://www.sciencedirect.com/science/article/pii/S2213231718305445 |