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Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study
Published on: July 27, 2016
Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the
Renaud Bussiere1, Alain Lacampagne2, Steven Reiken3
1From the Université Côte d'Azur, CNRS, IPMC, France, "Labex Distalz," 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France.
Abstract:
Alteration of ryanodine receptor (RyR)-mediated calcium (Ca2+) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca2+ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca2+ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid β (Aβ), β-adrenergic signaling, and altered Ca2+ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Aβ through a β2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances βAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca2+ leakage, or blocking the β2-adrenergic signaling cascade reduced βAPP processing and the production of Aβ in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca2+ leakage may be a therapeutic approach to treat AD.
Insights
Alzheimer disease (AD) involves altered calcium signaling. Targeting ryanodine receptor (RyR)-mediated calcium leakage, linked to amyloid beta, may offer a new therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Alterations in ryanodine receptor (RyR)-mediated calcium (Ca2+) signaling are implicated in Alzheimer disease (AD) models.
- The precise molecular mechanisms driving these Ca2+ signaling changes in AD are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms of altered RyR-mediated intracellular Ca2+ release in AD.
- To explore the role of post-translational modifications of RyR2 in AD pathogenesis.
- To examine the interplay between amyloid beta (Aβ), β-adrenergic signaling, and RyR2 function.
Main Methods:
- Utilized SH-SY5Y neuroblastoma cells expressing the familial Swedish mutation of the β-amyloid precursor protein (APPswe).
- Analyzed post-translational modifications (phosphorylation, oxidation, nitrosylation) of RyR2.
- Assessed RyR2 macromolecular complex remodeling and calstabin2 depletion.
- Investigated the effects of β2-adrenergic signaling cascade and PKA activation.
- Evaluated the impact of pharmacological stabilization of calstabin2 binding and β2-adrenergic signaling blockade.
Main Results:
- RyR2 undergoes post-translational modifications in APPswe-expressing cells.
- RyR2 macromolecular complex remodeling and calstabin2 depletion led to increased cytosolic Ca2+ and mitochondrial oxidative stress.
- Amyloid beta (Aβ) interacts with β-adrenergic signaling to alter Ca2+ signaling via leaky RyR2 channels.
- Post-translational modifications of RyR occur downstream of Aβ via a β2-adrenergic-PKA cascade, enhancing βAPP processing.
- Pharmacological interventions stabilizing RyR2 or blocking β2-adrenergic signaling reduced βAPP processing and Aβ production.
Conclusions:
- Post-translational modifications of RyR2 are a key mechanism in AD pathogenesis, downstream of Aβ.
- Targeting RyR-mediated Ca2+ leakage represents a potential therapeutic strategy for Alzheimer disease.
- Modulating β-adrenergic signaling offers a novel approach to reduce Aβ production in AD.
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