Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Alain Lacampagne; Xiaoping Liu; Steven Reiken; Renaud Bussiere; Albano C. Meli; Inger Lauritzen; Andrew F. Teich; Ran Zalk; Nathalie Saint; Ottavio Arancio; Charlotte Bauer; Fabrice Duprat; Clark A. Briggs; Shreaya Chakroborty; Grace E. Stutzmann; Michael L. Shelanski; Frederic Checler; Mounia Chami; Andrew R. Marks

doi:10.1007/s00401-017-1733-7

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Alain Lacampagne, Xiaoping Liu, Steven Reiken, Renaud Bussiere, Albano C. Meli, Inger Lauritzen, Andrew F. Teich, Ran Zalk, Nathalie Saint, Ottavio Arancio, Charlotte Bauer, Fabrice Duprat, Clark A. Briggs, Shreaya Chakroborty, Grace E. Stutzmann, Michael L. Shelanski, Frederic Checler, Mounia Chami, Andrew R. Marks

Research output: Contribution to journal › Article › peer-review

119 Scopus citations

Abstract

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP^+/−/PS1^+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca²⁺) leak. RyR-mediated ER Ca²⁺ leak activates Ca²⁺-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca²⁺ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

Original language	English
Pages (from-to)	749-767
Number of pages	19
Journal	Acta Neuropathologica
Volume	134
Issue number	5
DOIs	https://doi.org/10.1007/s00401-017-1733-7
State	Published - 1 Nov 2017
Externally published	Yes

Keywords

Amyloid beta
Calcium
Oxidative stress
PKA-dependent phosphorylation
Ryanodine receptor 2

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00401-017-1733-7

Cite this

Lacampagne, A., Liu, X., Reiken, S., Bussiere, R., Meli, A. C., Lauritzen, I., Teich, A. F., Zalk, R., Saint, N., Arancio, O., Bauer, C., Duprat, F., Briggs, C. A., Chakroborty, S., Stutzmann, G. E., Shelanski, M. L., Checler, F., Chami, M., & Marks, A. R. (2017). Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathologica, 134(5), 749-767. https://doi.org/10.1007/s00401-017-1733-7

@article{653f3ec4779148888b4a3e3afd46085d,

title = "Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer{\textquoteright}s disease-like pathologies and cognitive deficits",

abstract = "The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP+/−/PS1+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.",

keywords = "Amyloid beta, Calcium, Oxidative stress, PKA-dependent phosphorylation, Ryanodine receptor 2",

author = "Alain Lacampagne and Xiaoping Liu and Steven Reiken and Renaud Bussiere and Meli, {Albano C.} and Inger Lauritzen and Teich, {Andrew F.} and Ran Zalk and Nathalie Saint and Ottavio Arancio and Charlotte Bauer and Fabrice Duprat and Briggs, {Clark A.} and Shreaya Chakroborty and Stutzmann, {Grace E.} and Shelanski, {Michael L.} and Frederic Checler and Mounia Chami and Marks, {Andrew R.}",

note = "Publisher Copyright: {\textcopyright} 2017, Springer-Verlag Berlin Heidelberg.",

year = "2017",

month = nov,

day = "1",

doi = "10.1007/s00401-017-1733-7",

language = "English",

volume = "134",

pages = "749--767",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "5",

}

Lacampagne, A, Liu, X, Reiken, S, Bussiere, R, Meli, AC, Lauritzen, I, Teich, AF, Zalk, R, Saint, N, Arancio, O, Bauer, C, Duprat, F, Briggs, CA, Chakroborty, S, Stutzmann, GE, Shelanski, ML, Checler, F, Chami, M & Marks, AR 2017, 'Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits', Acta Neuropathologica, vol. 134, no. 5, pp. 749-767. https://doi.org/10.1007/s00401-017-1733-7

TY - JOUR

T1 - Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

AU - Lacampagne, Alain

AU - Liu, Xiaoping

AU - Reiken, Steven

AU - Bussiere, Renaud

AU - Meli, Albano C.

AU - Lauritzen, Inger

AU - Teich, Andrew F.

AU - Zalk, Ran

AU - Saint, Nathalie

AU - Arancio, Ottavio

AU - Bauer, Charlotte

AU - Duprat, Fabrice

AU - Briggs, Clark A.

AU - Chakroborty, Shreaya

AU - Stutzmann, Grace E.

AU - Shelanski, Michael L.

AU - Checler, Frederic

AU - Chami, Mounia

AU - Marks, Andrew R.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP+/−/PS1+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

AB - The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP+/−/PS1+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

KW - Amyloid beta

KW - Calcium

KW - Oxidative stress

KW - PKA-dependent phosphorylation

KW - Ryanodine receptor 2

UR - http://www.scopus.com/inward/record.url?scp=85021109953&partnerID=8YFLogxK

U2 - 10.1007/s00401-017-1733-7

DO - 10.1007/s00401-017-1733-7

M3 - Article

AN - SCOPUS:85021109953

SN - 0001-6322

VL - 134

SP - 749

EP - 767

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 5

ER -

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this