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      Autophagy is essential for hearing in mice

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Hearing loss is the most frequent sensory disorder in humans. Auditory hair cells (HCs) are postmitotic at late-embryonic differentiation and postnatal stages, and their damage is the major cause of hearing loss. There is no measurable HC regeneration in the mammalian cochlea, and the maintenance of cell function is crucial for preservation of hearing. Here we generated mice deficient in autophagy-related 5 ( Atg5), a gene essential for autophagy, in the HCs to investigate the effect of basal autophagy on hearing acuity. Deletion of Atg5 resulted in HC degeneration and profound congenital hearing loss. In autophagy-deficient HCs, polyubiquitinated proteins and p62/SQSTM1, an autophagy substrate, accumulated as inclusion bodies during the first postnatal week, and these aggregates increased in number. These findings revealed that basal autophagy has an important role in maintenance of HC morphology and hearing acuity.

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          The role of Atg proteins in autophagosome formation.

          Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi (2011)
          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.

            Kohei Kawamoto, Yehoash Raphael, Ryosei Minoda … (2005)
            In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.
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              Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma.

              Kunio Mizutari, Masato Fujioka, Makoto Hosoya … (2013)
              Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a γ-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-4889
                Publication date (Print): May 2017
                Publication date (Electronic): 11 May 2017
                Publication date PMC-release: 1 May 2017
                Volume: 8
                Issue: 5
                Page: e2780
                Affiliations
                [1 ]Department of Otolaryngology, Faculty of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
                [2 ]Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
                [3 ]Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University , 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
                [4 ]Department of Otolaryngology Head and Neck Surgery, Keio University , 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
                Author notes
                [* ]Department of Otolaryngology, Faculty of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 5800 8665; Fax: +81 3 3814 9486; E-mail: cfujimoto-tky@ 123456umin.ac.jp or tyamasoba-tky@ 123456umin.ac.jp
                Article
                Publisher Item ID: cddis2017194
                DOI: 10.1038/cddis.2017.194
                PMC ID: 5520715
                PubMed ID: 28492547
                SO-VID: 75d63925-fc91-4687-9ed5-45ee52b210e6
                Copyright © Copyright © 2017 The Author(s)
                License:

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 10 March 2017
                Date revision received : 24 March 2017
                Date accepted : 29 March 2017
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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