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Cyclin-dependent kinase 5, a node protein in diminished tauopathy: a systems biology approach.

Castro-Alvarez JF, Uribe-Arias SA, Mejía-Raigosa D, Cardona-Gómez GP - Front Aging Neurosci (2014)

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way.In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented.The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area, Faculty of Medicine, University of Antioquia, Sede de Investigación Universitaria Medellin, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

No MeSH data available.


Related in: MedlinePlus

Hypothetic model of CDK5 knockdown action on reversion of tauopathy in AD. The toxic events in AD induce imbalance between kinases and phosphatases, where CDK5 overactivation produce hyperphospholylation of Tau and neurodegeneration. Our in silico model can simulate it, when the calcium increase induces more phosphorylation of Tau. However, CDK5 Silencing in vivo and in silico supported CDK5 as a node protein diminished tauophaty through reversion of GSK3 β upregulation and preventing reduction of phosphatases.
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Figure 7: Hypothetic model of CDK5 knockdown action on reversion of tauopathy in AD. The toxic events in AD induce imbalance between kinases and phosphatases, where CDK5 overactivation produce hyperphospholylation of Tau and neurodegeneration. Our in silico model can simulate it, when the calcium increase induces more phosphorylation of Tau. However, CDK5 Silencing in vivo and in silico supported CDK5 as a node protein diminished tauophaty through reversion of GSK3 β upregulation and preventing reduction of phosphatases.

Mentions: This review shows the dynamic complexity of a cellular system that is in constant action. The scientific literature provides largely isolated experimental data combined with theoretical data capable of providing a specific cellular context. SB integrates experimental data and creates computational contexts limited by existing data but that is dynamic, inclusive and is able to create new questions to gain an understanding of biological phenomena. In our previous experimental results show a chronic disease model and the behavior of the molecular species after the decrease of CDK5 (Piedrahita et al., 2010; Castro-Alvarez et al., Submitted). Although more experiments are needed to determine the causality of the results, the computational model and the experimental results show the importance of GSK3β and PP2A in conjunction with CDK5 in the process of Tau hyperphosphorylation (Figure 7).


Cyclin-dependent kinase 5, a node protein in diminished tauopathy: a systems biology approach.

Castro-Alvarez JF, Uribe-Arias SA, Mejía-Raigosa D, Cardona-Gómez GP - Front Aging Neurosci (2014)

Hypothetic model of CDK5 knockdown action on reversion of tauopathy in AD. The toxic events in AD induce imbalance between kinases and phosphatases, where CDK5 overactivation produce hyperphospholylation of Tau and neurodegeneration. Our in silico model can simulate it, when the calcium increase induces more phosphorylation of Tau. However, CDK5 Silencing in vivo and in silico supported CDK5 as a node protein diminished tauophaty through reversion of GSK3 β upregulation and preventing reduction of phosphatases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150361&req=5

Figure 7: Hypothetic model of CDK5 knockdown action on reversion of tauopathy in AD. The toxic events in AD induce imbalance between kinases and phosphatases, where CDK5 overactivation produce hyperphospholylation of Tau and neurodegeneration. Our in silico model can simulate it, when the calcium increase induces more phosphorylation of Tau. However, CDK5 Silencing in vivo and in silico supported CDK5 as a node protein diminished tauophaty through reversion of GSK3 β upregulation and preventing reduction of phosphatases.
Mentions: This review shows the dynamic complexity of a cellular system that is in constant action. The scientific literature provides largely isolated experimental data combined with theoretical data capable of providing a specific cellular context. SB integrates experimental data and creates computational contexts limited by existing data but that is dynamic, inclusive and is able to create new questions to gain an understanding of biological phenomena. In our previous experimental results show a chronic disease model and the behavior of the molecular species after the decrease of CDK5 (Piedrahita et al., 2010; Castro-Alvarez et al., Submitted). Although more experiments are needed to determine the causality of the results, the computational model and the experimental results show the importance of GSK3β and PP2A in conjunction with CDK5 in the process of Tau hyperphosphorylation (Figure 7).

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way.In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented.The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area, Faculty of Medicine, University of Antioquia, Sede de Investigación Universitaria Medellin, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

No MeSH data available.


Related in: MedlinePlus