Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of des...

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Autores principales:	Yoshihide Nakamura, Takeshi Yamamoto, Xiaojuan Xu, Shigeki Kobayashi, Shinji Tanaka, Masaki Tamitani, Takashi Saito, Takaomi C. Saido, Masafumi Yano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2
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spelling	oai:doaj.org-article:c36d9860014d45d09b54d09dfaf5dbb22021-12-02T13:26:24ZEnhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease10.1038/s41598-021-86822-x2045-2322https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb22021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86822-xhttps://doaj.org/toc/2045-2322Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App NL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App NL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.Yoshihide NakamuraTakeshi YamamotoXiaojuan XuShigeki KobayashiShinji TanakaMasaki TamitaniTakashi SaitoTakaomi C. SaidoMasafumi YanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yoshihide Nakamura Takeshi Yamamoto Xiaojuan Xu Shigeki Kobayashi Shinji Tanaka Masaki Tamitani Takashi Saito Takaomi C. Saido Masafumi Yano Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
description	Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App NL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App NL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
format	article
author	Yoshihide Nakamura Takeshi Yamamoto Xiaojuan Xu Shigeki Kobayashi Shinji Tanaka Masaki Tamitani Takashi Saito Takaomi C. Saido Masafumi Yano
author_facet	Yoshihide Nakamura Takeshi Yamamoto Xiaojuan Xu Shigeki Kobayashi Shinji Tanaka Masaki Tamitani Takashi Saito Takaomi C. Saido Masafumi Yano
author_sort	Yoshihide Nakamura
title	Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
title_short	Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
title_full	Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
title_fullStr	Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
title_full_unstemmed	Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease
title_sort	enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in alzheimer disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2
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Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease

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