We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits.
- Authors
Lacampagne, Alain; Liu, Xiaoping; Reiken, Steven; Bussiere, Renaud; Meli, Albano; Lauritzen, Inger; Teich, Andrew; Zalk, Ran; Saint, Nathalie; Arancio, Ottavio; Bauer, Charlotte; Duprat, Fabrice; Briggs, Clark; Chakroborty, Shreaya; Stutzmann, Grace; Shelanski, Michael; Checler, Frederic; Chami, Mounia; Marks, Andrew
- 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 (Ca) leak. RyR-mediated ER Ca leak activates Ca-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca 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.
- Subjects
ALZHEIMER'S disease treatment; RYANODINE receptors; POST-translational modification; CELLULAR signal transduction; AMYLOID beta-protein
- Publication
Acta Neuropathologica, 2017, Vol 134, Issue 5, p749
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-017-1733-7