TY - JOUR T1 - Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway. JF - Redox Biol Y1 - 2018 A1 - Fetoni, Anna Rita A1 - Zorzi, Veronica A1 - Paciello, Fabiola A1 - Ziraldo, Gaia A1 - Peres, Chiara A1 - Raspa, Marcello A1 - Scavizzi, Ferdinando A1 - Salvatore, Anna Maria A1 - Crispino, Giulia A1 - Tognola, Gabriella A1 - Gentile, Giulia A1 - Spampinato, Antonio Gianmaria A1 - Cuccaro, Denis A1 - Guarnaccia, Maria A1 - Morello, Giovanna A1 - Van Camp, Guy A1 - Fransen, Erik A1 - Brumat, Marco A1 - Girotto, Giorgia A1 - Paludetti, Gaetano A1 - Gasparini, Paolo A1 - Cavallaro, Sebastiano A1 - Mammano, Fabio KW - Animals KW - Apoptosis KW - Connexin 26 KW - Female KW - Gene Deletion KW - Male KW - Mice KW - Mice, Inbred C57BL KW - NF-E2-Related Factor 2 KW - Oxidation-Reduction KW - Presbycusis KW - Signal Transduction AB -

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) 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.

VL - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30199819?dopt=Abstract ER -