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http://hdl.handle.net/1942/31403
Title: | Proteostasis is essential during cochlear development for neuron survival and hair cell polarity | Authors: | Freeman, Stephen Sanchez, Susana Mateo Pouyo, Ronald Van Lerberghe, Pierre-Bernard Hanon, Kevin Thelen, Nicolas Thiry, Marc MORELLI, Giovanni Van Hees, Laura Laguesse, Sophie Chariot, Alain Nguyen, Laurent Delacroix, Laurence Malgrange, Brigitte |
Issue Date: | 2019 | Publisher: | WILEY | Source: | EMBO reports (Print), 20 (9) (Art N° e47097) | Abstract: | Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age-related diseases, including hearing loss. Here, we show that altered proteostasis consequent to Elongator complex deficiency also impacts the proper development of the cochlea and results in deafness. In the absence of the catalytic subunit Elp3, differentiating spiral ganglion neurons display large aggresome-like structures and undergo apoptosis before birth. The cochlear mechanosensory cells are able to survive proteostasis disruption but suffer defects in polarity and stereociliary bundle morphogenesis. We demonstrate that protein aggregates accumulate at the apical surface of hair cells, where they cause a local slowdown of microtubular trafficking, altering the distribution of intrinsic polarity proteins and affecting kinocilium position and length. Alleviation of protein misfolding using the chemical chaperone 4-phenylbutyric acid during embryonic development ameliorates hair cell polarity in Elp3-deficient animals. Our study highlights the importance of developmental proteostasis in the cochlea and unveils an unexpected link between proteome integrity and polarized organization of cellular components. | Notes: | Freeman, S; Delacroix, L; Malgrange, B (reprint author), Univ Liege, CHU Sart Tilman, GIGA Neurosci Interdisciplinary Cluster Appl Geno, Liege, Belgium. sdfreeman@protonmail.com; ldelacroix@ulg.ac.be; bmalgrange@ulg.ac.be |
Keywords: | audition;ciliogenesis;microtubule;transport;tRNA-modifying enzyme | Document URI: | http://hdl.handle.net/1942/31403 | ISSN: | 1469-221X | e-ISSN: | 1469-3178 | DOI: | 10.15252/embr.201847097 | ISI #: | 000477227500001 | Rights: | 2019 The Authors. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2020 |
Appears in Collections: | Research publications |
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