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MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeos...

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Autores principales: Ikäheimo, Kuu, Herranen, Anni, Iivanainen, Vilma, Lankinen, Tuuli, Aarnisalo, Antti A, Sivonen, Ville, Patel, Kashyap A, Demir, Korcan, Saarma, Mart, Lindahl, Maria, Pirvola, Ulla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616558/
https://www.ncbi.nlm.nih.gov/pubmed/34815294
http://dx.doi.org/10.26508/lsa.202101068
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author Ikäheimo, Kuu
Herranen, Anni
Iivanainen, Vilma
Lankinen, Tuuli
Aarnisalo, Antti A
Sivonen, Ville
Patel, Kashyap A
Demir, Korcan
Saarma, Mart
Lindahl, Maria
Pirvola, Ulla
author_facet Ikäheimo, Kuu
Herranen, Anni
Iivanainen, Vilma
Lankinen, Tuuli
Aarnisalo, Antti A
Sivonen, Ville
Patel, Kashyap A
Demir, Korcan
Saarma, Mart
Lindahl, Maria
Pirvola, Ulla
author_sort Ikäheimo, Kuu
collection PubMed
description Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.
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spelling pubmed-86165582021-12-09 MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea Ikäheimo, Kuu Herranen, Anni Iivanainen, Vilma Lankinen, Tuuli Aarnisalo, Antti A Sivonen, Ville Patel, Kashyap A Demir, Korcan Saarma, Mart Lindahl, Maria Pirvola, Ulla Life Sci Alliance Research Articles Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans. Life Science Alliance LLC 2021-11-23 /pmc/articles/PMC8616558/ /pubmed/34815294 http://dx.doi.org/10.26508/lsa.202101068 Text en © 2021 Ikäheimo et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Ikäheimo, Kuu
Herranen, Anni
Iivanainen, Vilma
Lankinen, Tuuli
Aarnisalo, Antti A
Sivonen, Ville
Patel, Kashyap A
Demir, Korcan
Saarma, Mart
Lindahl, Maria
Pirvola, Ulla
MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title_full MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title_fullStr MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title_full_unstemmed MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title_short MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
title_sort manf supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616558/
https://www.ncbi.nlm.nih.gov/pubmed/34815294
http://dx.doi.org/10.26508/lsa.202101068
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