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Start Over Author "Guarnaccia, M" Publisher elsevier bv
10 results on '"Guarnaccia, M"'

10. Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Author

Fabio Mammano, Veronica Zorzi, Gaia Ziraldo, Giovanna Morello, Anna Maria Salvatore, Maria Guarnaccia, Anna Rita Fetoni, Gaetano Paludetti, Denis Cuccaro, Guy Van Camp, Giulia Gentile, Fabiola Paciello, Marco Brumat, Antonio Gianmaria Spampinato, Erik Fransen, Giulia Crispino, Chiara Peres, Sebastiano Cavallaro, Ferdinando Scavizzi, Gabriella Tognola, Marcello Raspa, Paolo Gasparini, Giorgia Girotto, Fetoni, Anna Rita, Zorzi, Veronica, Paciello, Fabiola, Ziraldo, Gaia, Peres, Chiara, Raspa, Marcello, Scavizzi, Ferdinando, Salvatore, Anna Maria, Crispino, Giulia, Tognola, Gabriella, Gentile, Giulia, Spampinato, Antonio Gianmaria, Cuccaro, Deni, Guarnaccia, Maria, Morello, Giovanna, Van Camp, Guy, Fransen, Erik, Brumat, Marco, Girotto, Giorgia, Paludetti, Gaetano, Gasparini, Paolo, Cavallaro, Sebastiano, Mammano, Fabio, Fetoni, Ar, Zorzi, V, Paciello, F, Ziraldo, G, Peres, C, Raspa, M, Scavizzi, F, Salvatore, Alba Maria Rita, Crispino, G, Tognola, G, Gentile, Giuseppe, Spampinato, Ag, Cuccaro, D, Guarnaccia, M, Morello, G, Van Camp, G, Fransen, E, Brumat, M, Girotto, G, Paludetti, G, Gasparini, P, Cavallaro, S, and Mammano, F.

Subjects
Male, 0301 basic medicine, Clinical Biochemistry, Connexin, Presbycusis, Apoptosis, Cochlear duct, Inbred C57BL, Hair cells, Mouse models, medicine.disease_cause, Biochemistry, Mice, lcsh:QH301-705.5, Regulation of gene expression, lcsh:R5-920, Chemistry, Cell biology, Connexin 26, medicine.anatomical_structure, Age-related hearing lo, Settore MED/32 - AUDIOLOGIA, Female, Hair cell, medicine.symptom, Signal transduction, lcsh:Medicine (General), Spiral ganglion neurons, Oxidation-Reduction, Research Paper, Signal Transduction, Age-related hearing loss, Genome-wide association study, Animals, Gene Deletion, Mice, Inbred C57BL, NF-E2-Related Factor 2, Organic Chemistry, Hearing loss, Settore BIO/09 - FISIOLOGIA, Mouse model, PRKCE Gene, 03 medical and health sciences, otorhinolaryngologic diseases, medicine, Biology, medicine.disease, 030104 developmental biology, lcsh:Biology (General), Oxidative stress
Abstract

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., Graphical abstract fx1, Highlights • Partial loss of Cx26 accelerates hearing impairment progression in Gjb2+/- mice. • The auditory organ is affected by increased apoptosis due to redox imbalance. • The expression of several genes controlled by the Nrf2/ARE pathway is deregulated. • Genome-wide association detected two of these genes in humans with presbycusis. • This work sheds new light on the etiopathogenesis of presbycusis and its prevention.

Published
2018

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