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

Autor: 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
Přispěvatelé: 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, Mammano, F.
Rok vydání: 2018
Předmět:
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
Zdroj: Redox Biology, Vol 19, Iss, Pp 301-317 (2018)
RedoxBiology 19 (2018): 301–317. doi:10.1016/j.redox.2018.08.002
info:cnr-pdr/source/autori: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/titolo:Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway/doi:10.1016%2Fj.redox.2018.08.002/rivista:RedoxBiology/anno:2018/pagina_da:301/pagina_a:317/intervallo_pagine:301–317/volume:19
Redox Biology
ISSN: 2213-2317
DOI: 10.1016/j.redox.2018.08.002
Popis: 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.
Databáze: OpenAIRE
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