Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage

Neuropathie auditive (identification du gène DFNB59 et physiopathologie)

Par une analyse de liaison génétique dans des grandes familles iraniennes atteintes de surdité prélinguale de transmission autosomique récessive, j ai pu définir deux nouveaux loci de surdité isolée: DFNB40, sur le chromosome 22 (22q11.21-12.1) et DFNB59, sur le chromosome 2 (2q31.1-31.3). J ai ensuite identifié le gène DFNB59. Il code pour une nouvelle protéine de 352 acides aminés, que j ai nommée pejvakine. Afin de valider l implication de ce gène dans la surdité DFNB59, j ai produit un modèle de souris knock-in pour l une des deux mutations humaines identifiées. Ces souris ont une neuropathie auditive traduisant un dysfonctionnement des neurones de la voie auditive afférente. DFNB59 est le premier gène responsable de neuropathie auditive rétrocochléaire identifié. La production des souris knock-out pour Dfnb59 est en cours. Elle devrait nous aider à mieux comprendre le rôle de la pejvakine ainsi que le processus pathogénique associé à la forme génétique de surdité correspondante.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

International audienceHearing impairment is the most frequent sensory deficit in humans of all age groups, from children (1/500) to the elderly (more than 50% of the over-75 s). Over 50% of congenital deafness are hereditary in nature. The other major causes of deafness, which also may have genetic predisposition, are aging, acoustic trauma, ototoxic drugs such as aminoglycosides, and noise exposure. Over the last two decades, the study of inherited deafness forms and related animal models has been instrumental in deciphering the molecular, cellular, and physiological mechanisms of disease. However, there is still no curative treatment for sensorineural deafness. Hearing loss is currently palliated by rehabilitation methods: conventional hearing aids, and for more severe forms, cochlear implants. Efforts are continuing to improve these devices to help users to understand speech in noisy environments and to appreciate music. However, neither approach can mediate a full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelia. New therapeutic approaches based on gene transfer and gene editing tools are being developed in animal models. In this review, we focus on the successful restoration of auditory and vestibular functions in certain inner ear conditions, paving the way for future clinical applications

The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

International audienceUsher syndrome (USH) is the most common cause of deaf–blindness in humans, with a prevalence of about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are currently used to reduce the burden of hearing loss in severe-to-profoundly deaf patients, but many promising treatments including gene, cell, and drug therapies to restore the native function of the inner ear and retinal sensory cells are under investigation. The traditional clinical classification of Usher syndrome defines three major subtypes—USH1, 2 and 3—according to hearing loss severity and onset, the presence or absence of vestibular dysfunction, and age at onset of retinitis pigmentosa. Pathogenic variants of nine USH genes have been initially reported: MYO7A, USH1C, PCDH15, CDH23 , and USH1G for USH1, USH2A, ADGRV1, and WHRN for USH2, and CLRN1 for USH3. Based on the co-occurrence of hearing and vision deficits, the list of USH genes has been extended to few other genes, but with limited supporting information. A consensus on combined criteria for Usher syndrome is crucial for the development of accurate diagnosis and to improve patient management. In recent years, a wealth of information has been obtained concerning the properties of the Usher proteins, related molecular networks, potential genotype–phenotype correlations, and the pathogenic mechanisms underlying the impairment or loss of hearing, balance and vision. The advent of precision medicine calls for a clear and more precise diagnosis of Usher syndrome, exploiting all the existing data to develop a combined clinical/genetic/network/functional classification for Usher syndrome

Déficience auditive induite par le bruit : comment peut-elle être prévenue et traitée ?

National audienceSelon l’Organisation mondiale de la santé, 466 millions d'individus dont 34 millions d’enfants présentent une déficience auditive handicapante, et un milliard de personnes seront touchées en 2050. Ces atteintes ont des causes multiples, peuvent survenir à tout âge et avoir des degrés de sévérité et de progression variables. Notre environnement devenant de plus en plus bruyant, les sources de nuisances sonores allant croissantes, l’exposition au bruit occupe malheureusement une place de plus en plus importante comme cause de perte d'audition. Bien qu’évitables, ces atteintes ont un impact économique et sociétal très important. En effet, l’exposition prolongée au bruit ou à des sons de forte intensité peut entraîner des dommages irréversibles aux cellules sensorielles et aux neurones auditifs, ce qui détériore la perception auditive et perturbe l’intelligibilité de la parole

Combination of pejvakin and LC3B for treating hearing losses

publication date: 2020-05-28; filing date: 2018-11-19The balance between peroxisome biogenesis and degradation is crucial for redox cell homeostasis. The present invention is based on the findings that pejvakin is involved in the early and rapid selective autophagic degradation of peroxisome (pexophagy) in auditory hair cells subjected to sound overstimulation, by interacting with the autophagosome-associated protein MAP1LC3B. It is here demonstrated that it is possible to completely restore sound-induced pexophagy and to prevent oxidative stress in Pjvk-/- auditory hair cells by transducing in same the Pejvakin and MAP1LC3B proteins together. Thus, the present invention relates to compositions containing these two proteins, or gene vectors encoding same, as well as their therapeutic use for preventing and/or treating presbycusis, noise-induced hearing-loss or sudden sensorineural hearing loss or auditory damages induced by acoustic trauma or ototoxic substances, or hereditary hearing loss due to an altered expression level of Pejvakin or to an altered DFNB59 gene expression, in a subject in need thereof

Hypervulnerability to sound-exposure through impaired adaptive proliferation of peroxisomes

A deficiency of pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of deafness. Pejvakin-deficient (Pjvk-/-) mice also exhibited variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggested a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation showed that the cochlear sensory hair cells and auditory pathway neurons of Pjvk-/- mice and patients were exceptionally vulnerable to sound. Pjvk-/- cochleas displayed features of marked oxidative stress and impaired anti-oxidant defenses. We showed that pejvakin is associated with peroxisomes, and is required for the oxidative stress-induced proliferation of these organelles. In Pjvk-/- hair cells, peroxisomes displayed structural abnormalities after the onset of hearing. Noise-exposure of wild-type mice rapidly upregulated Pjvk cochlear transcription, and triggered peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the anti-oxidant activity of peroxisomes protects the auditory system against noise-induced damage. Pjvk gene transfer can rescue auditory dysfunction in Pjvk-/- mice

Noise-induced hearing loss due to impaired proliferation of peroxisomes

A deficiency of pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of deafness. Pejvakin-deficient (Pjvk-/-) mice also exhibited variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggested a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation showed that the cochlear sensory hair cells and auditory pathway neurons of Pjvk-/- mice and patients were exceptionally vulnerable to sound. Pjvk-/- cochleas displayed features of marked oxidative stress and impaired anti-oxidant defenses. We showed that pejvakin is associated with peroxisomes, and is required for the oxidative stress-induced proliferation of these organelles. In Pjvk-/- hair cells, peroxisomes displayed structural abnormalities after the onset of hearing. Noise-exposure of wild-type mice rapidly upregulated Pjvk cochlear transcription, and triggered peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the anti-oxidant activity of peroxisomes protects the auditory system against noise-induced damage. Pjvk gene transfer can rescue auditory dysfunction in Pjvk-/- mice.ANR – NKTH “HearDeafTreat” 2010 - INTB - 1402-01; French state program ‘‘Investissements d’Avenir’’ (ANR-10-LABX-65)

Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage

International audienceNoise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakin-deficient (Pjvk -/-), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubule-associated protein 1 light chain 3β) to peroxisomes in wild-type, but not Pjvk -/-, mice. We also show that pejvakin-LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin-LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk -/- mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins