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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Published in:Scientific Reports
Main Authors: Yoshihide Nakamura, Takeshi Yamamoto, Xiaojuan Xu, Shigeki Kobayashi, Shinji Tanaka, Masaki Tamitani, Takashi Saito, Takaomi C. Saido, Masafumi Yano
Format: Article in Journal/Newspaper
Language:English
Published: Nature Portfolio 2021
Subjects:
R
Q
Online Access:https://doi.org/10.1038/s41598-021-86822-x
https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2
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spelling ftdoajarticles:oai:doaj.org/article:c36d9860014d45d09b54d09dfaf5dbb2 2023-05-15T15:06:37+02:00 Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease Yoshihide Nakamura Takeshi Yamamoto Xiaojuan Xu Shigeki Kobayashi Shinji Tanaka Masaki Tamitani Takashi Saito Takaomi C. Saido Masafumi Yano 2021-03-01T00:00:00Z https://doi.org/10.1038/s41598-021-86822-x https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2 EN eng Nature Portfolio https://doi.org/10.1038/s41598-021-86822-x https://doaj.org/toc/2045-2322 doi:10.1038/s41598-021-86822-x 2045-2322 https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2 Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) Medicine R Science Q article 2021 ftdoajarticles https://doi.org/10.1038/s41598-021-86822-x 2022-12-31T05:23:57Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Scientific Reports 11 1
institution Open Polar
collection Directory of Open Access Journals: DOAJ Articles
op_collection_id ftdoajarticles
language English
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
topic_facet Medicine
R
Science
Q
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 in Journal/Newspaper
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://doi.org/10.1038/s41598-021-86822-x
https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2
geographic Arctic
geographic_facet Arctic
genre Arctic
genre_facet Arctic
op_source Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
op_relation https://doi.org/10.1038/s41598-021-86822-x
https://doaj.org/toc/2045-2322
doi:10.1038/s41598-021-86822-x
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https://doaj.org/article/c36d9860014d45d09b54d09dfaf5dbb2
op_doi https://doi.org/10.1038/s41598-021-86822-x
container_title Scientific Reports
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