1. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits
- Author
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Alain Lacampagne, Andrew R. Marks, Steven Reiken, Clark A. Briggs, Xiaoping Liu, Ottavio Arancio, Andrew F. Teich, Shreaya Chakroborty, Charlotte Bauer, Michael L. Shelanski, Nathalie Saint, Inger Lauritzen, Fabrice Duprat, Grace E. Stutzmann, Mounia Chami, Frédéric Checler, Ran Zalk, Renaud Bussiere, Albano C. Meli, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Department of Physiology & Cellular Biophysics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Chicago Medical School [Rosalind Franklin University], Rosalind Franklin University, Department of Neuroscience Rosalind Franklin University, Rosalind Franklin University-Chicago Medical Scchool, Università degli Studi di Ferrara (UniFE), and Columbia University College of Physicians and Surgeons
- Subjects
Male ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Ryanodine receptor 2 ,Mice ,0302 clinical medicine ,Phosphorylation ,ComputingMilieux_MISCELLANEOUS ,biology ,Ryanodine receptor ,Nitrosylation ,PKA-dependent phosphorylation ,musculoskeletal system ,Sarcoplasmic Reticulum ,cardiovascular system ,Female ,Alzheimer's disease ,Signal transduction ,tissues ,medicine.medical_specialty ,Amyloid beta ,Mice, Transgenic ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Humans ,Calcium Signaling ,Maze Learning ,Endoplasmic reticulum ,Recognition, Psychology ,Ryanodine Receptor Calcium Release Channel ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,030104 developmental biology ,Endocrinology ,Oxidative stress ,Synaptic plasticity ,biology.protein ,Calcium ,Neurology (clinical) ,Cognition Disorders ,Protein Processing, Post-Translational ,Neuroscience ,030217 neurology & neurosurgery - 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.
- Published
- 2017
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