Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

Abstract Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hear...

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Autores principales:	Mustafa N. Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L. Croteau, Matthew W. Kelley, Vilhelm A. Bohr
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/a055efe507754e63b3c4e985a862155b
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spelling	oai:doaj.org-article:a055efe507754e63b3c4e985a862155b2021-12-02T14:23:46ZShort-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome10.1038/s41514-019-0040-z2056-3973https://doaj.org/article/a055efe507754e63b3c4e985a862155b2020-01-01T00:00:00Zhttps://doi.org/10.1038/s41514-019-0040-zhttps://doaj.org/toc/2056-3973Abstract Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (CSA −/− and CSB m/m ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD+, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD+ levels are reduced in the cochlea of CSB m/m mice and that short-term treatment (10 days) with the NAD+ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSB m/m mice. Similar, but more modest effects were observed in CSA −/− mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA −/− and CSB m/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD+ supplementation rescues reduced synaptic ribbon formation in both CSA −/− and CSB m/m mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.Mustafa N. OkurBeatrice MaoRisako KimuraScott HaraczyTracy FitzgeraldKamren Edwards-HollingsworthJane TianWasif OsmaniDeborah L. CroteauMatthew W. KelleyVilhelm A. BohrNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 6, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Mustafa N. Okur Beatrice Mao Risako Kimura Scott Haraczy Tracy Fitzgerald Kamren Edwards-Hollingsworth Jane Tian Wasif Osmani Deborah L. Croteau Matthew W. Kelley Vilhelm A. Bohr Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
description	Abstract Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (CSA −/− and CSB m/m ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD+, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD+ levels are reduced in the cochlea of CSB m/m mice and that short-term treatment (10 days) with the NAD+ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSB m/m mice. Similar, but more modest effects were observed in CSA −/− mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA −/− and CSB m/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD+ supplementation rescues reduced synaptic ribbon formation in both CSA −/− and CSB m/m mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.
format	article
author	Mustafa N. Okur Beatrice Mao Risako Kimura Scott Haraczy Tracy Fitzgerald Kamren Edwards-Hollingsworth Jane Tian Wasif Osmani Deborah L. Croteau Matthew W. Kelley Vilhelm A. Bohr
author_facet	Mustafa N. Okur Beatrice Mao Risako Kimura Scott Haraczy Tracy Fitzgerald Kamren Edwards-Hollingsworth Jane Tian Wasif Osmani Deborah L. Croteau Matthew W. Kelley Vilhelm A. Bohr
author_sort	Mustafa N. Okur
title	Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
title_short	Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
title_full	Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
title_fullStr	Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
title_full_unstemmed	Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
title_sort	short-term nad+ supplementation prevents hearing loss in mouse models of cockayne syndrome
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/a055efe507754e63b3c4e985a862155b
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Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

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