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Proteostasis is essential during cochlear development for neuron survival and hair cell polarity.

EMBO reports (2019-07-20)
Stephen Freeman, Susana Mateo Sánchez, Ronald Pouyo, Pierre-Bernard Van Lerberghe, Kevin Hanon, Nicolas Thelen, Marc Thiry, Giovanni Morelli, Laura Van Hees, Sophie Laguesse, Alain Chariot, Laurent Nguyen, Laurence Delacroix, Brigitte Malgrange

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.

Product Number
Product Description

MG-132, Ready Made Solution, ≥90% (HPLC)
Anti-β-Actin−Peroxidase antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Monoclonal Anti-Tubulin, Acetylated antibody produced in mouse, clone 6-11B-1, ascites fluid
Anti-Neurofilament NF-H Antibody, clone TA51, culture supernatant, clone TA51, Chemicon®
Anti-Glutamate Receptor 2 & 3 Antibody, Chemicon®, from rabbit
Anti-Digoxigenin-AP, Fab fragments, from sheep
Ribonucleic acid, transfer from baker's yeast (S. cerevisiae), Type X-SA, lyophilized powder
Sodium phenylbutyrate, ≥98% (HPLC)