Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy
Abstract:Abnormal deposition of the microtubule-associated protein tau is a common pathological feature of multiple neurodegenerative diseases, including Alzheimer's disease (AD), and plays critical roles in their pathogenesis. Disruption of calcium homeostasis and the downstream kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) coincides with pathological phosphorylation of tau in AD brains. However, it remains unclear whether and how dysregulation of CaMKII affects tau toxicity. Using a Drosophila model, we… Show more
“…Another study showed that CaMKII dysregulation in Alzheimer’s patients may be a modulator of toxicity in Alzheimer’s disease, a dementia characterized by aberrant calcium signaling, synapse and neuronal loss, and impaired memory 60 . A Different study showed that disruption of calcium homeostasis and the downstream kinase CaMKII coincides with pathological phosphorylation of tau in AD brains 61 .Fig. 5S-nitrosylation alters the non-canonical Wnt/calcium signaling pathway.Right side: SNO of RYR lead to Ca++ release from the ER.…”
Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice. We found major changes in the S-nitrosoproteome between the groups in both regions. Several pathways converged to show that calcium regulation and non-canonical Wnt signaling are affected using GO and pathway analysis. Significant increase in 3-nitrotyrosine was found in the CA1 and entorhinal cortex regions, which indicates an elevation of oxidative stress and nitric oxide formation. There was evidence of increased Non-Canonical Wnt/Ca++ (NC-WCa) signaling in the cortex of the P301S mice; including increases in phosphorylated CaMKII, and S-nitrosylation of E3 ubiquitin-protein ligase RNF213 (RNF-213) leading to increased levels of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, which further amplify the NC-WCa and contribute to the pathology. These findings implicate activation of the NC-WCa pathway in tauopathy and provide novel insights into the contribution of S-nitrosylation to NC-WCa activation, and offer new potential drug targets for treatment of tauopathies.
“…Another study showed that CaMKII dysregulation in Alzheimer’s patients may be a modulator of toxicity in Alzheimer’s disease, a dementia characterized by aberrant calcium signaling, synapse and neuronal loss, and impaired memory 60 . A Different study showed that disruption of calcium homeostasis and the downstream kinase CaMKII coincides with pathological phosphorylation of tau in AD brains 61 .Fig. 5S-nitrosylation alters the non-canonical Wnt/calcium signaling pathway.Right side: SNO of RYR lead to Ca++ release from the ER.…”
Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice. We found major changes in the S-nitrosoproteome between the groups in both regions. Several pathways converged to show that calcium regulation and non-canonical Wnt signaling are affected using GO and pathway analysis. Significant increase in 3-nitrotyrosine was found in the CA1 and entorhinal cortex regions, which indicates an elevation of oxidative stress and nitric oxide formation. There was evidence of increased Non-Canonical Wnt/Ca++ (NC-WCa) signaling in the cortex of the P301S mice; including increases in phosphorylated CaMKII, and S-nitrosylation of E3 ubiquitin-protein ligase RNF213 (RNF-213) leading to increased levels of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, which further amplify the NC-WCa and contribute to the pathology. These findings implicate activation of the NC-WCa pathway in tauopathy and provide novel insights into the contribution of S-nitrosylation to NC-WCa activation, and offer new potential drug targets for treatment of tauopathies.
“…Although this result is discrepant with many early observations on clinico-phosphorylation status correlation, there is at least one tau phosphorylation site located at residue Thr 205 and recognized by antibody AT8, for which increased stoichiometry of phosphorylation exerts a beneficial/protective effect in the prevention or neutralization of Aβ toxicity [48]. The other potential phospho-acceptor sites typically associated with tau hyperphosphorylation and toxicity include Ser 9 , Ser 26 , Thr 175 , Ser 199 , Thr 231 , Ser 262 , Ser 356 and Ser 396 [49–51]. Ser 396 was also increased by TYROBP deficiency, suggesting that multiple competing effects are occurring simultaneously, indicating that the beneficial effects are apparently sufficiently robust to overcome the competing detrimental effects.…”
TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer’s disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in
MAPT
P301S
;
Tyrobp
-/-
mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in
MAPT
P301S
;
Tyrobp
-/-
mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.
“…CaM is implicated in the regulation of MAPs activity through two complementary mechanisms: firstly, this CBP can control the activity of kinases and phosphatases that act on these cytoskeletal proteins, as exemplified by Ca 2+ /CaM-dependent kinases’ control of tau phosphorylation [160,163,164,165]; secondly, CaM can directly bind to both MAP-2 and tau with a flip-flop mechanism by which CaM binding prevents the association of MAPs and microtubules in a Ca 2+ -dependent manner, thereby destabilizing microtubules [166,167,168]. Interestingly, in the neurons of C. aspersum , both CaM- and P-Tau-like immunoreactivity showed the co-localization of strongly immunopositive masses during hibernation, suggesting a stage-specific interaction that could either be direct or involve the mediation of kinases, which may increase the levels of P-Tau and result in decreased binding to microtubules [133].…”
Section: Cbps In the Hibernating Nervous System: A Role In Neuroprmentioning
Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive in cold environments; it relies on molecular, cellular, and behavioral adaptations guided by the neuroendocrine system that together ensure unmatched tolerance to hypothermia, hypometabolism, and hypoxia. Therefore, hibernation is a useful model to study molecular neuroprotective adaptations to extreme conditions, and can reveal useful applications to human pathological conditions. In this review, we describe the known changes in Ca2+-signaling and the detection and activity of CBPs in the nervous system of vertebrate and invertebrate models during hibernation, focusing on cytosolic Ca2+ buffers and calmodulin. Then, we discuss these findings in the context of the neuroprotective and neural plasticity mechanisms in the central nervous system: in particular, those associated with cytoskeletal proteins. Finally, we compare the expression of CBPs in the hibernating nervous system with two different conditions of neurodegeneration, i.e., platinum-induced neurotoxicity and Alzheimer’s disease, to highlight the similarities and differences and demonstrate the potential of hibernation to shed light into part of the molecular mechanisms behind neurodegenerative diseases.
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