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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

Variation in the levels of Tau and pTau in response to variations in calcium levels. Levels were increased 2-fold (0.2 μM), 10-fold (1 μM), and 100-fold (10 μM). The inset in the graph shows the relative increase of pTau compared with the basal condition.
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Figure 4: Variation in the levels of Tau and pTau in response to variations in calcium levels. Levels were increased 2-fold (0.2 μM), 10-fold (1 μM), and 100-fold (10 μM). The inset in the graph shows the relative increase of pTau compared with the basal condition.

Mentions: After evaluating Tau and pTau levels at basal conditions, calcium levels were increased by 2-, 10-, and 100-fold from an initial concentration of 0.1 μM. Thus, an unbalanced condition of calcium homeostasis or an excitotoxic process, which is characteristic of pathological processes, was simulated. With increasing calcium concentration, pTau increased, reaching even a 28% increase over the initial condition (Figure 4). This indicates that calcium levels are a key factor in Tau phosphorylation; a significant increase in calcium influences the activity of CDK5 by activating calpains and promoting p25/CDK5 complex formation, which then has the ability to phosphorylate Tau over a longer period of time.


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)

Variation in the levels of Tau and pTau in response to variations in calcium levels. Levels were increased 2-fold (0.2 μM), 10-fold (1 μM), and 100-fold (10 μM). The inset in the graph shows the relative increase of pTau compared with the basal condition.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Variation in the levels of Tau and pTau in response to variations in calcium levels. Levels were increased 2-fold (0.2 μM), 10-fold (1 μM), and 100-fold (10 μM). The inset in the graph shows the relative increase of pTau compared with the basal condition.
Mentions: After evaluating Tau and pTau levels at basal conditions, calcium levels were increased by 2-, 10-, and 100-fold from an initial concentration of 0.1 μM. Thus, an unbalanced condition of calcium homeostasis or an excitotoxic process, which is characteristic of pathological processes, was simulated. With increasing calcium concentration, pTau increased, reaching even a 28% increase over the initial condition (Figure 4). This indicates that calcium levels are a key factor in Tau phosphorylation; a significant increase in calcium influences the activity of CDK5 by activating calpains and promoting p25/CDK5 complex formation, which then has the ability to phosphorylate Tau over a longer period of time.

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